内质网应激介导的心肌凋亡与心力衰竭的机制研究
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摘要
内质网(endoplasmic reticulum，ER)是真核细胞Ca~(2+)储存、脂类合成、蛋白折叠和修饰的重要细胞器，任何影响内质网功能的因素诱发的内质网内非折叠蛋白蓄积(unfolded protein response，UPR)都能导致内质网应激(ER stress)。内质网应激是应激后细胞内的最初反应，是线粒体氧化应激等细胞应激反应的共同初始通路。内质网应激是细胞一种保护性反应，用以减少非折叠蛋白的蓄积，恢复内质网正常功能；但若应激持续，促生存机制向促凋亡途径转变，细胞则发生凋亡。有研究报道，内质网应激反应与众多导致心力衰竭的心血管疾病如动脉粥样硬化、心肌缺血和扩张型心肌病等密切相关，但其具体的作用机制仍了解很少。本研究对心力衰竭中内质网应激反应的具体激活情况、传导途径进行了探索，我们明确了心力衰竭中内质网应激反应被激活，内质网应激诱导的凋亡通路启动，证实并推测了内质网应激在心力衰竭中的激活诱因、传导途径和效应机制。
首先，我们用Western免疫印迹检测发现，在晚期心力衰竭行心脏移植术患者的心脏组织中，存在GRP78激活、PERK-eIF2α通路激活和JNKs通路激活的现象，表明在人类慢性心力衰竭中，内质网应激反应激活。
然后，我们用两种模拟人类心肌肥大心力衰竭的大鼠模型，压力负荷(腹主动脉缩窄，AAC)与β_1肾上腺素受体持久兴奋(异丙肾上腺素(isoproterenol，Iso)注射)模型，来研究心力衰竭中内质网应激反应的具体途径；并给予选择性β_1受体阻滞剂美托洛尔(metoprolol)干预。通过心脏形态学、病理学、血流动力学检测，发现压力负荷与β_1肾上腺素受体持久兴奋诱导大鼠心肌肥大、左室功能受损，模型制作成功。用Western免疫印迹、免疫组织化学方法和TUNEL凋亡检测发现，心肌肥大心力衰竭大鼠心脏中，内质网分子伴侣GRP78被激活，负责内质网蛋白质控的KDEL受体分子表达大量增加，内质网应激反应IRE1-XBP1途径激活，内质网特异性诱导凋亡的转录因子CHOP表达增加，细胞凋亡增多；用选择性β_1受体阻滞剂美托洛尔干预后，部分抑制了上述途径，心肌凋亡减少，心肌肥大减轻，心功能改善。因此我们可以初步认为压力负荷和β_1肾上腺素受体持久激活诱导了心脏内质网应激，继而引发了心肌细胞凋亡、心肌肥大和心力衰竭。
为了验证β_1受体激活是否诱导细胞内质网应激反应，阻断β_1受体能否抑制内质网应激，我们在培养的H9c2(2-1)心肌细胞中给予β_1受体激动剂异丙肾上腺素(Iso)刺激24小时，发现GRP78表达显著增加；预先给予细胞PKA特异性抑制剂PKI、CaMKIIδ特异性抑制剂KN93、以及选择性β_1受体阻滞剂美托洛尔和非选择性β受体阻滞剂普萘洛尔(propranolol)孵育1小时，然后给予Iso刺激，24小时后，我们发现PKI、KN93、美托洛尔干预组GRP78表达与Iso组相比无明显变化，普萘洛尔预先干预组GRP78表达比单纯Iso刺激组明显减少。说明Iso激活β_1受体兴奋诱发的内质网应激可能并不通过传统的PKA或CaMKIIδ途径；非选择性β受体阻滞剂普萘洛尔下调Iso刺激产生的内质网分子伴侣。
接着我们使用内质网应激诱导剂毒胡萝卜素(TG)和衣霉素(TM)刺激心肌细胞产生内质网应激，通过Western Blots免疫印迹检测、Hoechst凋亡染色和Anexin V／PI凋亡检测，结果发现与单用TG或TM刺激组相比，美托洛尔组GRP78表达减少，细胞凋亡减轻；普萘洛尔组在24小时的时候，几乎完全阻断了GRP78的表达和抑制了内质网特异的致凋亡效应器caspase-12激活。接着我们用无β受体阻断作用却同样有膜稳定作用的右旋普萘洛尔和仅具有膜稳定作用的钠离子通道阻滞剂美西律干预细胞，发现同样有抑制内质网应激反应及减轻相关凋亡的作用。提示普萘洛尔抑制内质网应激的机制可能独立于β受体阻滞作用之外，与其膜稳定作用有关。
为了进一步在体内证实膜稳定作用与内质网应激反应相关，我们选取兼具膜稳定作用的非选择性β受体阻滞剂普萘洛尔，和一种典型的膜稳定剂(钠离子通道阻滞剂)美西律(mexiletine)干预压力负荷大鼠(AAC)，发现心肌肥大心力衰竭大鼠心脏GRP78表达减少、PERK-eIF2α途径抑制和CHOP蛋白表达阻断，提示内质网应激反应减轻，细胞凋亡抑制；同时有β受体阻断作用的普萘洛尔减轻了心肌肥大，两者都改善了AAC大鼠左心功能。我们推测在心力衰竭中阻断β受体、抑制钠离子内流增多，可以减轻心肌内质网应激，减少凋亡。
上面的研究发现膜稳定剂在体内体外均抑制了内质网应激，并改善了心脏功能，而膜稳定作用实际上是维持细胞钠离子稳态的结果，为了研究内质网应激反应与钠离子活动的关系，我们用一种钠通道激活剂藜芦定(veratridine)刺激H9c2(2-1)细胞，30分钟时GRP78表达增加；24小时时PERK磷酸化和CHOP蛋白表达显著增加，说明钠离子通道过度激活诱发了内质网应激反应。预先给予细胞一种特异的钠离子通道阻断剂河豚毒(tetrodotoxin，TTX)孵育1小时，再分别用TG、TM刺激24小时，结果发现GRP78表达明显减少，磷酸化PERK和CHOP表达被TTX完全阻断，说明阻滞钠通道过度激活能有效阻断内质网应激反应。以上结果提示钠离子通道活动在内质网应激反应中起重要作用。
总之我们对心力衰竭中内质网应激反应作用机制和途径进行了系统的研究，初步揭示了心力衰竭中内质网应激反应与β_1受体持久激活、细胞Na~+内流增多有关。内质网应激反应通过诱导应激分子GRP78，激活PERK-eIF2α和IRE1-XBP1途径，诱导CHOP表达、促使caspase-12活化和激活JNKs通路，引起心肌细胞凋亡而导致心肌肥大心力衰竭。给予β受体阻滞剂和膜稳定剂在体内体外都能有效抑制内质网应激，减少细胞凋亡。内质网应激反应途径的关键分子，可能成为心力衰竭治疗和诊断的靶点，对心力衰竭发生发展的基础研究和临床防治有积极意义。
The endoplasmic reticulum (ER) is a central organelle of each eukaryotic cell as theplace of calcium storage,lipid synthesis,protein folding and protein maturation.Disturbances in any of these functions such as accumulation of unfolded protein (unfoldedprotein response,UPR) or excessive protein traffic can lead to so-called ER stress.ERstress is the initial cell response to stress and the common pathway leading to manyintracellular stress responses,such as oxidative stress in mitochondria.ER stress is apro-survival response to reduce the accumulation of unfolded proteins and restore normalER function.However,if stress prolongs,signaling switches from pro-survival topro-apoptotic.It has been reported that ER stress is involved in many heart diseases thatcontribute to heart failure at last,including artherosclerosis,myocardial ischemia,dilatedcardiomyopathy.However,the exact mechanisms of ER stress interfering with heart failurestill remain unclear.This study investigated the inducement and signaling pathway of ERstress in failing heart.We found that heart failure really induced ER stress and theER-initiated apoptosis,and confirm the inducement,pathway and interaction of ER stressin heart failure.
We went first to confirm the induction of ER stress in human failing heart from hearttransplant recipients by Western Blots analysis,evaluated by GRP78 increase,PERK-eIF2αpathway and JNKs pathway activation.
Then we use two kinds of rattus models with cardiac hypertrophy and heart failure,overload pressure (abdominal aortic constriction,AAC) and sustainedβ_1-adrenergic stimulation (isoproterenol injection,Iso),to investigate the exact pathway of ER stress inheart failure.And we treated the experiment animals with metoprolol,a selectiveβ_1 blocker.By examination of morphology,pathology,and hemodynamics,we found cardiachypertrophy and left ventricular function impairment induced by overload pressure orchronicβ_1-adrenergic stimulation.And compared with control groups,ER stress wasincreased in the failing hearts of both AAC and Iso rattus,evaluated by increase of GRP78,activation of IRE1-XBP1 and induction of CHOP,by analysis of Western Blots.And wefound KDEL positive cells increased in AAC rattus hearts by histochemical analysis.TUNEL examination showed more apoptosis cells in Iso rattus hearts.Treatment ofmetoprolol attenuated ER stress and apoptosis as well as improving hypertrophy and leftventricular function.The data indicates that overload pressure or sustainedβ_1-adrenergicstimulation induce ER stress leading to cardiomyocytes apoptosis,cardiac hypertrophy andheart failure.
To investigate whetherβ_1-adrenergic stimulation induces ER stress,we treatedH9c2(2-1) cells with isoproterenol (Iso) for 24 hours,and found GRP78 expressionincreased.We pretreated H9c2(2-1) cells with PKI,a specific inhibitor of PKA,KN93,aspecific inhibitor of CaMKⅡδ,metoprolol or propranolol for 1 hour before exposing themto Iso.After 24 hours,we found that there was no significant change of GRP78 proteinlevel in PKI,KN93 and metoprolol,but pretreatment of propranolol reduced GRP78expression induced by Iso.It revealed that ER stress induced byβ_1-adrenergic stimulationmay not go through the typical PKA pathway or CaMKⅡδpathway.It may be some wayindependent.Nonselectiveβ-blocker propranolol down-regulation the ER chaperonsinduced by Iso.
We pretreated H9c2(2-1) cells with metoprolol or propranolol before exposing them toER stressor TG or TM.By Western Blots analyses,Hoechst staining and Anexin V/PIapoptosis tests,we found pretreatment of metoprolol partially reduced GRP78 andattenuated apoptosis.And propranolol nearly completely cut off the GRP78 and inhibited the activation of pro-caspase-12.We next examined the effect of the propranolol isomerD-propranolol,which compared to L-isomer is approximately 50-fold less potent as aβ-adrenoceptor antagonist,but also plays as a membrane-stabilizer,as well as mexiletine,which is a membrane stabilizer,but not a beta-blocker.We found they also attenuated ERstress and inhibited apoptosis pathway.These data supports that the effect ofpropranolol toattenuate ER stress is dependent of itsβ-blockage.It may be associated with its effects asmembrane stabilizer.
To investigate the association of membrane stability and ER stress,we administrateAAC rattus with propranolol or mexiletine.We found that treatment with propranolol andmexiletine both reduced ER stress,assessed by GRP78 decrease,PERK-eIF2αpathwayinhibition,and CHOP reduction.They both improve the left ventricular function of AACrattus,and propranolol attenuated cardiac hypertrophy.We presumed thatβblockade andinhibition of increase Na+ influx in heart failure may attenuate ER stress and decreaseapoptosis.
As noted above,membrane-stabilizers unexpectedly improved the heart function andprevented ER stress both in vivo and in cultured cells.We know that the membranestability depends on the sodium homeostasis in fact.To investigate whether ER stress isassociated with sodium channel action,which determins the membrane stability,wepretreated H9c2(2-1) cells with veratridine,a sodium channel activator.GRP78 wasincrease at 30 min,and phosphorylated PERK and CHOP significantly increase after 24hours,suggesting that activation of sodium channel induced ER stress.We then pretreatedcells with TTX (tetrodotoxin),a specific sodium channel blocker,before adding TG or TM.It showed that GRP78 was remarkably decrease and expression of phosphorylated PERKand CHOP was blocked completely.The data yielded evidence that inhibition ofoveractivation of sodium channel blocked ER stress effectually.Taken together,the datasupposed that sodium channel action played an important role in ER stress.
In summary,we have systemically investigated the mechanisms and pathway of ER stress in heart failure.We propose that ER stress is associated with sustainedβ_1-adrenergicstimulation and intracellular Na~+ increase in heart failure.ER stress induces cardiomyocytesapoptosis by activation of ER chaperons such as GRP78 and CHOP,PERK-eIF2αpathway,IRE1-XBP1 pathway,caspase-12 and JNKs pathway.Blockade of the key molecular of ERstress signaling pathway can inhibit heart failure,suggesting that it is a potential target fordiagnosis and treatment of heart failure.
首先，我们用Western免疫印迹检测发现，在晚期心力衰竭行心脏移植术患者的心脏组织中，存在GRP78激活、PERK-eIF2α通路激活和JNKs通路激活的现象，表明在人类慢性心力衰竭中，内质网应激反应激活。
然后，我们用两种模拟人类心肌肥大心力衰竭的大鼠模型，压力负荷(腹主动脉缩窄，AAC)与β_1肾上腺素受体持久兴奋(异丙肾上腺素(isoproterenol，Iso)注射)模型，来研究心力衰竭中内质网应激反应的具体途径；并给予选择性β_1受体阻滞剂美托洛尔(metoprolol)干预。通过心脏形态学、病理学、血流动力学检测，发现压力负荷与β_1肾上腺素受体持久兴奋诱导大鼠心肌肥大、左室功能受损，模型制作成功。用Western免疫印迹、免疫组织化学方法和TUNEL凋亡检测发现，心肌肥大心力衰竭大鼠心脏中，内质网分子伴侣GRP78被激活，负责内质网蛋白质控的KDEL受体分子表达大量增加，内质网应激反应IRE1-XBP1途径激活，内质网特异性诱导凋亡的转录因子CHOP表达增加，细胞凋亡增多；用选择性β_1受体阻滞剂美托洛尔干预后，部分抑制了上述途径，心肌凋亡减少，心肌肥大减轻，心功能改善。因此我们可以初步认为压力负荷和β_1肾上腺素受体持久激活诱导了心脏内质网应激，继而引发了心肌细胞凋亡、心肌肥大和心力衰竭。
为了验证β_1受体激活是否诱导细胞内质网应激反应，阻断β_1受体能否抑制内质网应激，我们在培养的H9c2(2-1)心肌细胞中给予β_1受体激动剂异丙肾上腺素(Iso)刺激24小时，发现GRP78表达显著增加；预先给予细胞PKA特异性抑制剂PKI、CaMKIIδ特异性抑制剂KN93、以及选择性β_1受体阻滞剂美托洛尔和非选择性β受体阻滞剂普萘洛尔(propranolol)孵育1小时，然后给予Iso刺激，24小时后，我们发现PKI、KN93、美托洛尔干预组GRP78表达与Iso组相比无明显变化，普萘洛尔预先干预组GRP78表达比单纯Iso刺激组明显减少。说明Iso激活β_1受体兴奋诱发的内质网应激可能并不通过传统的PKA或CaMKIIδ途径；非选择性β受体阻滞剂普萘洛尔下调Iso刺激产生的内质网分子伴侣。
接着我们使用内质网应激诱导剂毒胡萝卜素(TG)和衣霉素(TM)刺激心肌细胞产生内质网应激，通过Western Blots免疫印迹检测、Hoechst凋亡染色和Anexin V／PI凋亡检测，结果发现与单用TG或TM刺激组相比，美托洛尔组GRP78表达减少，细胞凋亡减轻；普萘洛尔组在24小时的时候，几乎完全阻断了GRP78的表达和抑制了内质网特异的致凋亡效应器caspase-12激活。接着我们用无β受体阻断作用却同样有膜稳定作用的右旋普萘洛尔和仅具有膜稳定作用的钠离子通道阻滞剂美西律干预细胞，发现同样有抑制内质网应激反应及减轻相关凋亡的作用。提示普萘洛尔抑制内质网应激的机制可能独立于β受体阻滞作用之外，与其膜稳定作用有关。
为了进一步在体内证实膜稳定作用与内质网应激反应相关，我们选取兼具膜稳定作用的非选择性β受体阻滞剂普萘洛尔，和一种典型的膜稳定剂(钠离子通道阻滞剂)美西律(mexiletine)干预压力负荷大鼠(AAC)，发现心肌肥大心力衰竭大鼠心脏GRP78表达减少、PERK-eIF2α途径抑制和CHOP蛋白表达阻断，提示内质网应激反应减轻，细胞凋亡抑制；同时有β受体阻断作用的普萘洛尔减轻了心肌肥大，两者都改善了AAC大鼠左心功能。我们推测在心力衰竭中阻断β受体、抑制钠离子内流增多，可以减轻心肌内质网应激，减少凋亡。
上面的研究发现膜稳定剂在体内体外均抑制了内质网应激，并改善了心脏功能，而膜稳定作用实际上是维持细胞钠离子稳态的结果，为了研究内质网应激反应与钠离子活动的关系，我们用一种钠通道激活剂藜芦定(veratridine)刺激H9c2(2-1)细胞，30分钟时GRP78表达增加；24小时时PERK磷酸化和CHOP蛋白表达显著增加，说明钠离子通道过度激活诱发了内质网应激反应。预先给予细胞一种特异的钠离子通道阻断剂河豚毒(tetrodotoxin，TTX)孵育1小时，再分别用TG、TM刺激24小时，结果发现GRP78表达明显减少，磷酸化PERK和CHOP表达被TTX完全阻断，说明阻滞钠通道过度激活能有效阻断内质网应激反应。以上结果提示钠离子通道活动在内质网应激反应中起重要作用。
总之我们对心力衰竭中内质网应激反应作用机制和途径进行了系统的研究，初步揭示了心力衰竭中内质网应激反应与β_1受体持久激活、细胞Na~+内流增多有关。内质网应激反应通过诱导应激分子GRP78，激活PERK-eIF2α和IRE1-XBP1途径，诱导CHOP表达、促使caspase-12活化和激活JNKs通路，引起心肌细胞凋亡而导致心肌肥大心力衰竭。给予β受体阻滞剂和膜稳定剂在体内体外都能有效抑制内质网应激，减少细胞凋亡。内质网应激反应途径的关键分子，可能成为心力衰竭治疗和诊断的靶点，对心力衰竭发生发展的基础研究和临床防治有积极意义。
The endoplasmic reticulum (ER) is a central organelle of each eukaryotic cell as theplace of calcium storage,lipid synthesis,protein folding and protein maturation.Disturbances in any of these functions such as accumulation of unfolded protein (unfoldedprotein response,UPR) or excessive protein traffic can lead to so-called ER stress.ERstress is the initial cell response to stress and the common pathway leading to manyintracellular stress responses,such as oxidative stress in mitochondria.ER stress is apro-survival response to reduce the accumulation of unfolded proteins and restore normalER function.However,if stress prolongs,signaling switches from pro-survival topro-apoptotic.It has been reported that ER stress is involved in many heart diseases thatcontribute to heart failure at last,including artherosclerosis,myocardial ischemia,dilatedcardiomyopathy.However,the exact mechanisms of ER stress interfering with heart failurestill remain unclear.This study investigated the inducement and signaling pathway of ERstress in failing heart.We found that heart failure really induced ER stress and theER-initiated apoptosis,and confirm the inducement,pathway and interaction of ER stressin heart failure.
We went first to confirm the induction of ER stress in human failing heart from hearttransplant recipients by Western Blots analysis,evaluated by GRP78 increase,PERK-eIF2αpathway and JNKs pathway activation.
Then we use two kinds of rattus models with cardiac hypertrophy and heart failure,overload pressure (abdominal aortic constriction,AAC) and sustainedβ_1-adrenergic stimulation (isoproterenol injection,Iso),to investigate the exact pathway of ER stress inheart failure.And we treated the experiment animals with metoprolol,a selectiveβ_1 blocker.By examination of morphology,pathology,and hemodynamics,we found cardiachypertrophy and left ventricular function impairment induced by overload pressure orchronicβ_1-adrenergic stimulation.And compared with control groups,ER stress wasincreased in the failing hearts of both AAC and Iso rattus,evaluated by increase of GRP78,activation of IRE1-XBP1 and induction of CHOP,by analysis of Western Blots.And wefound KDEL positive cells increased in AAC rattus hearts by histochemical analysis.TUNEL examination showed more apoptosis cells in Iso rattus hearts.Treatment ofmetoprolol attenuated ER stress and apoptosis as well as improving hypertrophy and leftventricular function.The data indicates that overload pressure or sustainedβ_1-adrenergicstimulation induce ER stress leading to cardiomyocytes apoptosis,cardiac hypertrophy andheart failure.
To investigate whetherβ_1-adrenergic stimulation induces ER stress,we treatedH9c2(2-1) cells with isoproterenol (Iso) for 24 hours,and found GRP78 expressionincreased.We pretreated H9c2(2-1) cells with PKI,a specific inhibitor of PKA,KN93,aspecific inhibitor of CaMKⅡδ,metoprolol or propranolol for 1 hour before exposing themto Iso.After 24 hours,we found that there was no significant change of GRP78 proteinlevel in PKI,KN93 and metoprolol,but pretreatment of propranolol reduced GRP78expression induced by Iso.It revealed that ER stress induced byβ_1-adrenergic stimulationmay not go through the typical PKA pathway or CaMKⅡδpathway.It may be some wayindependent.Nonselectiveβ-blocker propranolol down-regulation the ER chaperonsinduced by Iso.
We pretreated H9c2(2-1) cells with metoprolol or propranolol before exposing them toER stressor TG or TM.By Western Blots analyses,Hoechst staining and Anexin V/PIapoptosis tests,we found pretreatment of metoprolol partially reduced GRP78 andattenuated apoptosis.And propranolol nearly completely cut off the GRP78 and inhibited the activation of pro-caspase-12.We next examined the effect of the propranolol isomerD-propranolol,which compared to L-isomer is approximately 50-fold less potent as aβ-adrenoceptor antagonist,but also plays as a membrane-stabilizer,as well as mexiletine,which is a membrane stabilizer,but not a beta-blocker.We found they also attenuated ERstress and inhibited apoptosis pathway.These data supports that the effect ofpropranolol toattenuate ER stress is dependent of itsβ-blockage.It may be associated with its effects asmembrane stabilizer.
To investigate the association of membrane stability and ER stress,we administrateAAC rattus with propranolol or mexiletine.We found that treatment with propranolol andmexiletine both reduced ER stress,assessed by GRP78 decrease,PERK-eIF2αpathwayinhibition,and CHOP reduction.They both improve the left ventricular function of AACrattus,and propranolol attenuated cardiac hypertrophy.We presumed thatβblockade andinhibition of increase Na+ influx in heart failure may attenuate ER stress and decreaseapoptosis.
As noted above,membrane-stabilizers unexpectedly improved the heart function andprevented ER stress both in vivo and in cultured cells.We know that the membranestability depends on the sodium homeostasis in fact.To investigate whether ER stress isassociated with sodium channel action,which determins the membrane stability,wepretreated H9c2(2-1) cells with veratridine,a sodium channel activator.GRP78 wasincrease at 30 min,and phosphorylated PERK and CHOP significantly increase after 24hours,suggesting that activation of sodium channel induced ER stress.We then pretreatedcells with TTX (tetrodotoxin),a specific sodium channel blocker,before adding TG or TM.It showed that GRP78 was remarkably decrease and expression of phosphorylated PERKand CHOP was blocked completely.The data yielded evidence that inhibition ofoveractivation of sodium channel blocked ER stress effectually.Taken together,the datasupposed that sodium channel action played an important role in ER stress.
In summary,we have systemically investigated the mechanisms and pathway of ER stress in heart failure.We propose that ER stress is associated with sustainedβ_1-adrenergicstimulation and intracellular Na~+ increase in heart failure.ER stress induces cardiomyocytesapoptosis by activation of ER chaperons such as GRP78 and CHOP,PERK-eIF2αpathway,IRE1-XBP1 pathway,caspase-12 and JNKs pathway.Blockade of the key molecular of ERstress signaling pathway can inhibit heart failure,suggesting that it is a potential target fordiagnosis and treatment of heart failure.
引文
1.Harding, H.P., Calfon, M., Urano, F., Novoa, I. & Ron, D. Transcriptional and translational control in the Mammalian unfolded protein response. Annual review of cell and developmental biology 18, 575-599 (2002).
2.Kaufman, R.J. Orchestrating the unfolded protein response in health and disease. The Journal of clinical investigation 110, 1389-1398 (2002).
3. Schroder, M. & Kaufman, R.J. ER stress and the unfolded protein response. Mutation research 569, 29-63 (2005).
4. Schroder, M. & Kaufman, R.J. The mammalian unfolded protein response. Annual review of biochemistry 74, 739-789 (2005).
5. Shi, Y., et al. Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control. Molecular and cellular biology 18, 7499-7509 (1998).
6.Harding, H.P., Zhang, Y. & Ron, D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 397, 271-274 (1999).
7.Iwawaki, T., et al. Translational control by the ER transmembrane kinase/ribonuclease IRE1 under ER stress. Nature cell biology 3, 158-164 (2001).
8.Tirasophon, W., Welihinda, A.A. & Kaufman, R.J. A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells. Genes & development 12,1812-1824(1998).
9. Wang, X.Z., et al. Cloning of mammalian Ire1 reveals diversity in the ER stress responses. The EMBO journal 17, 5708-5717 (1998).
10. Bertolotti, A., Zhang, Y., Hendershot, L.M., Harding, H.P. & Ron, D. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nature cell biology 2, 326-332 (2000).
11. Yoshida, H., Matsui, T., Yamamoto, A., Okada, T. & Mori, K. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107, 881-891 (2001).
12. Nishitoh, H., et al. ASK1 is essential for JNK/SAPK activation by TRAF2. Molecular cell 2, 389-395(1998).
13. Zinszner, H., et al. CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes & development 12, 982-995 (1998).
14. Distelhorst, C.W. & McCormick, T.S. Bcl-2 acts subsequent to and independent of Ca2+ fluxes to inhibit apoptosis in thapsigargin- and glucocorticoid-treated mouse lymphoma cells. Cell calcium 19, 473-483 (1996).
15. Wei, M.C., et al. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science (New York, N.Y292, 727-730 (2001).
16. Boya, P., Cohen, I., Zamzami, N., Vieira, H.L. & Kroemer, G. Endoplasmic reticulum stress-induced cell death requires mitochondrial membrane permeabilization. Cell death and differentiation 9, 465-467 (2002).
17. Hacki, J., et al. Apoptotic crosstalk between the endoplasmic reticulum and mitochondria controlled by Bcl-2. Oncogene 19, 2286-2295 (2000).
18. Bassik, M.C., Scorrano, L., Oakes, S.A., Pozzan, T. & Korsmeyer, S.J. Phosphorylation of BCL-2 regulates ER Ca2+ homeostasis and apoptosis. The EMBO journal 23, 1207-1216(2004).
19. Nakagawa, T., et al. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 403, 98-103 (2000).
20. Okada, K., et al Prolonged endoplasmic reticulum stress in hypertrophic and failing heart after aortic constriction: possible contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis. Circulation 110, 705-712 (2004).
21. Szegezdi, E., et al. ER stress contributes to ischemia-induced cardiomyocyte apoptosis. Biochemical and biophysical research communications 349, 1406-1411 (2006).
22. Myoishi, M., et al. Increased endoplasmic reticulum stress in atherosclerotic plaques associated with acute coronary syndrome. Circulation 116, 1226-1233 (2007).
23. Levy, D., et al. Long-term trends in the incidence of and survival with heart failure.The New England journal of medicine 347, 1397-1402 (2002).
24. Kerkela, R., et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nature medicine 12, 908-916 (2006).
25. Simonian, M.H. & Smith, J.A. Spectrophotometric and colorimetric determination of protein concentration. Current protocols in molecular biology / edited by Frederick M. Ausubel... [et al Chapter 10, Unit 10 11A (2006).
26. Yoshida, H., Haze, K., Yanagi, H., Yura, T. & Mori, K. Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins. Involvement of basic leucine zipper transcription factors. The Journal of biological chemistry 273, 33741-33749 (1998).
27.Marx, J. Cell biology. A stressful situation. Science (New York, N.Y 313, 1564-1566(2006).
28.Davis, R.J. Signal transduction by the JNK group of MAP kinases. Cell 103, 239-252(2000).
29.Greenberg, B. Treatment of heart failure: state of the art and prospectives. Journal of cardiovascular pharmacology 38 Suppl 2, S59-63 (2001).
30. Hasegawa, K.,Iwai-Kanai,E.&Sasayama,S.Neurohormonal regulation of myocardial cell apoptosis during the development of heart failure. Journal of cellular physiology 186, 11-18 (2001).
31.Paull,J.R. &Widdop,R.E.Persistent cardiovascular effects of chronic renin-angiotensin system inhibition following withdrawal in adult spontaneously hypertensive rats. Journal of hypertension 19, 1393-1402 (2001).
32.Molkentin, J.D. & Dorn, G.W., 2nd. Cytoplasmic signaling pathways that regulate cardiac hypertrophy. Annual review of physiology 63, 391-426 (2001).
33.Colucci, W.S. Molecular and cellular mechanisms of myocardial failure. The American journal of cardiology 80, 15L-25L (1997).
34.Givertz, M.M. & Colucci, W.S. New targets for heart-failure therapy: endothelin, inflammatory cytokines, and oxidative stress. Lancet 352 Suppl 1, SI34-38 (1998).
35.Yoshida, H. ER stress and diseases. The FEBS journal 274, 630-658 (2007).
36.Austin, R.C., Lentz, S.R. & Werstuck, G.H. Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease. Cell death and differentiation 11 Suppl 1, S56-64 (2004).
37.Lawrence de Koning, A.B., Werstuck, G.H., Zhou, J. & Austin, R.C Hyperhomocysteinemia and its role in the elopment of atherosclerosis. Clinical biochemistry 36, 431 -441 (2003).
38. Outinen, P.A., et al. Homocysteine-induced endoplasmic reticulum stress and growth arrest leads to specific changes in gene expression in human vascular endothelial cells. Blood 94, 959-967(1999).
39. Huang, R.F., Huang, S.M., Lin, B.S., Wei, J.S. & Liu, T.Z. Homocysteine thiolactone induces apoptotic DNA damage mediated by increased intracellular hydrogen peroxide and caspase 3 activation in HL-60 cells. Life sciences 68, 2799-2811 (2001).
40.Zhang, C., et al. Homocysteine induces programmed cell death in human vascular endothelial cells through activation of the unfolded protein response. The Journal of biological chemistry 276, 35867-35874 (2001).
41. Zhou, J., et al. Dietary supplementation with methionine and homocysteine promotes early atherosclerosis but not plaque rupture in ApoE-deficient mice. Arteriosclerosis, thrombosis, and vascular biology 21, 1470-1476 (2001).
42. Hofmann, M.A., et al. Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model. The Journal of clinical investigation 107,675-683(2001).
43. Devries-Seimon, T., et al. Cholesterol-induced macrophage apoptosis requires ER stress pathways and engagement of the type A scavenger receptor. The Journal of cell biology 171, 61-73(2005).
44. Feng, B., et al. The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages. Nature cell biology 5, 781-792 (2003).
45. Han, S., et al. Macrophage insulin receptor deficiency increases ER stress-induced apoptosis and necrotic core formation in advanced atherosclerotic lesions. Cell metabolism 3, 257-266 (2006).
46. Majors, A.K., et al. Endoplasmic reticulum stress induces hyaluronan deposition and leukocyte adhesion. The Journal of biological chemistry 278, 47223-47231 (2003).
47. Yamamoto, K., et al. The KDEL receptor modulates the endoplasmic reticulum stress response through mitogen-activated protein kinase signaling cascades. The Journal of biological chemistry 278, 34525-34532 (2003).
48. Hamada, H., et al. Dilated cardiomyopathy caused by aberrant endoplasmic reticulum quality control in mutant KDEL receptor transgenic mice. Molecular and cellular biology 24, 8007-8017 (2004).
49. Frey, N. & Olson, E.N. Cardiac hypertrophy: the good, the bad, and the ugly. Annual review of physiology 65, 45-79 (2003).
50. Frey, N., Katus, H.A., Olson, E.N. & Hill, J.A. Hypertrophy of the heart: a new therapeutic target? Circulation 109, 1580-1589 (2004).
51. Eichhorn, E.J. & Bristow, M.R. Medical therapy can improve the biological properties of the chronically failing heart. A new era in the treatment of heart failure. Circulation 94,2285-2296(1996).
52. Massie, B.M. 15 years of heart-failure trials: what have we learned? Lancet 352 Suppl 1, SI29-33 (1998).
53. Bristow, M.R. Why does the myocardium fail? Insights from basic science. Lancet 352 Suppl 1, SI8-14 (1998).
54. Consensus recommendations for the management of chronic heart failure. On behalf of the membership of the advisory council to improve outcomes nationwide in heart failure. The American journal of cardiology S3, 1A-38A (1999).
55. Bristow, M.R. & Gilbert, E.M. Improvement in cardiac myocyte function by biological effects of medical therapy: a new concept in the treatment of heart failure. European heart journal 16 Suppl F, 20-31 (1995).
56. Marano, G., Palazzesi, S., Fadda, A., Vergari, A. & Ferrari, A.U. Attenuation of aortic banding-induced cardiac hypertrophy by propranolol is independent of beta-adrenoceptor blockade. Journal of hypertension 20, 763-769 (2002).
57. Oelze, M., et al. Nebivolol inhibits superoxide formation by NADPH oxidase and endothelial dysfunction in angiotensin Ⅱ-treated rats. Hypertension 48, 677-684(2006).
58. Nirmala, C. & Puvanakrishnan, R. Protective role of curcumin against isoproterenol induced myocardial infarction in rats. Molecular and cellular biochemistry 159, 85-93(1996).
59. Shioura, K.M., Geenen, D.L. & Goldspink, P.H. Assessment of cardiac function with the pressure-volume conductance system following myocardial infarction in mice. American journal of physiology 293, H2870-2877 (2007).
60. Samsamshariat, S.A., Hashemzadeh, M., Samsamshariat, Z. & Movahed, M.R. Cardiovascular and hemodynamic effect of polyethylene glycol in rats. Cardiovasc Revasc Med 6, 70-72 (2005).
61. Pacher, P., et al. Left ventricular pressure-volume relationship in a rat model of advanced aging-associated heart failure. American journal of physiology 287, H2132-2137 (2004).
62. Rao, R.V., et al. Coupling endoplasmic reticulum stress to the cell death program: role of the ER chaperone GRP78. FEBS letters 514, 122-128 (2002).
63. Xu, C., Bailly-Maitre, B. & Reed, J.C. Endoplasmic reticulum stress: cell life and death decisions. The Journal of clinical investigation 115, 2656-2664 (2005).
64. Lee, A.H., Iwakoshi, N.N. & Glimcher, L.H. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Molecular and cellular biology 23, 7448-7459 (2003).
65. Yan, W., et al. Control of PERK eIF2alpha kinase activity by the endoplasmic reticulum stress-induced molecular chaperone P58IPK. Proceedings of the National Academy of Sciences of the United States of America 99, 15920-15925 (2002).
66. Hatai, T., et al. Execution of apoptosis signal-regulating kinase 1 (ASK1)-induced apoptosis by the mitochondria-dependent caspase activation. The Journal of biological chemistry 275, 26576-26581 (2000).
67. Nishitoh, H., et al. ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes & development 16, 1345-1355 (2002).
68. Urano, F., et al. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science (New York, N. Y 287, 664-666 (2000).
69. Zhu, W.Z., et al. Linkage of beta1-adrenergic stimulation to apoptotic heart cell death through protein kinase A-independent activation of Ca2+/calmodulin kinase Ⅱ. The Journal of clinical investigation 111, 617-625 (2003).
70. Wang, W., et al. Sustained betal-adrenergic stimulation modulates cardiac contractility by Ca2+/calmodulin kinase signaling pathway. Circulation research 95, 798-806 (2004).
71. Abraham, W.T. Switching between beta blockers in heart failure patients: rationale and practical considerations. Congestive heart failure (Greenwich, Conn 9, 271-278(2003).
72. Communal, C., Singh, K., Pimentel, D.R. & Colucci, W.S. Norepinephrine stimulates apoptosis in adult rat ventricular myocytes by activation of the beta-adrenergic pathway. Circulation 98, 1329-1334 (1998).
73. Iwai-Kanai, E., et al. alpha- and beta-adrenergic pathways differentially regulate cell type-specific apoptosis in rat cardiac myocytes. Circulation 100, 305-311 (1999).
74. Zheng, M., Han, Q.D. & Xiao, R.P. Distinct beta-adrenergic receptor subtype signaling in the heart and their pathophysiological relevance. Sheng Li Xue Bao 56, 1-15(2004).
75. Saraste, A., et al. Apoptosis in human acute myocardial infarction. Circulation 95, 320-323 (1997).
76. Zhu, W.Z., et al. Dual modulation of cell survival and cell death by beta(2)-adrenergic signaling in adult mouse cardiac myocytes. Proceedings of the National Academy of Sciences of the United States of America 98, 1607-1612 (2001).
77. Lohse, M.J., Engelhardt, S. & Eschenhagen, T. What is the role of beta-adrenergic signaling in heart failure? Circulation research 93, 896-906 (2003).
78. Saito, S., et al. beta-Adrenergic pathway induces apoptosis through calcineurin activation in cardiac myocytes. The Journal of biological chemistry 275, 34528-34533(2000).
79. Matsuda, J.J., Lee, H. & Shibata, E.F. Enhancement of rabbit cardiac sodium channels by beta-adrenergic stimulation. Circulation research 70, 199-207 (1992).
80. Ono, K., Fozzard, H.A. & Hanck, D.A. Mechanism of cAMP-dependent modulation of cardiac sodium channel current kinetics. Circulation research 72, 807-815 (1993).
81. Moorman, J.R., Kirsch, G.E., Lacerda, A.E. & Brown, A.M. Angiotensin Ⅱ modulates cardiac Na+ channels in neonatal rat. Circulation research 65, 1804-1809 (1989).
82. Abraham, W.T., et al. Cardiac resynchronization in chronic heart failure. The New England journal of medicine 346, 1845-1853 (2002).
83. Mankad, S.,et al. Combined angiotensin Ⅱ receptor antagonism and angiotensin-converting enzyme inhibition further attenuates postinfarction left ventricular remodeling. Circulation 103, 2845-2850 (2001).
84. Orrenius, S., Zhivotovsky, B. & Nicotera, P. Regulation of cell death: the calcium-apoptosis link. Nat Rev Mol Cell Biol 4, 552-565 (2003).
85. Kent, R.L., Hoober, J.K. & Cooper, G.t. Load responsiveness of protein synthesis in adult mammalian myocardium: role of cardiac deformation linked to sodium influx. Circulation research 64, 74-85 (1989).
86. Kent, R.L., Mann, D.L. & Cooper, G.t. Signals for cardiac muscle hypertrophy in hypertension. Journal of cardiovascular pharmacology 17 Suppl 2, S7-13 (1991).
87. Yaoita, H., Sakabe, A., Maehara, K. & Maruyama, Y. Different effects of carvedilol, metoprolol, and propranolol on left ventricular remodeling after coronary stenosis or after permanent coronary occlusion in rats. Circulation 105, 975-980 (2002).
88. Laird, J.M., Carter, A.J., Grauert, M. & Cervero, F. Analgesic activity of a novel use-dependent sodium channel blocker, crobenetine, in mono-arthritic rats. British journal of pharmacology 134, 1742-1748 (2001).
89. Despa, S., Islam, M.A., Weber, C.R., Pogwizd, S.M. & Bers, D.M. Intracellular Na(+) concentration is elevated in heart failure but Na/K pump function is unchanged. Circulation 105, 2543-2548 (2002).
90. Baartscheer, A. & van Borren, M.M. Sodium ion transporters as new therapeutic targets in heart failure. Cardiovascular & hematological agents in medicinal chemistry 6, 229-236 (2008).
91. Nakamura, T.Y., Iwata, Y., Arai, Y., Komamura, K. & Wakabayashi, S. Activation of Na+/H+ exchanger 1 is sufficient to generate Ca2+ signals that induce cardiac hypertrophy and heart failure. Circulation research 103, 891-899 (2008).
92. Baartscheer, A. Chronic inhibition of na(+)/h(+)-exchanger in the heart. Current vascular pharmacology 4, 23-29 (2006).
93. Doggrell, S.A. & Hancox, J.C. Is timing everything? Therapeutic potential of modulators of cardiac Na(+) transporters. Expert opinion on investigational drugs 12, 1123-1142(2003).
94. Andersen, G.O., et al. Increased expression and function of the myocardial Na-K-2Cl cotransporter in failing rat hearts. Basic research in cardiology 101, 471-478 (2006).
95. Ramasamy, R., Payne, J.A., Whang, J., Bergmann, S.R. & Schaefer, S. Protection of ischemic myocardium in diabetics by inhibition of electroneutral Na+-K+-2C1-cotransporter. American journal of physiology 281, H515-522 (2001).
96. Baartscheer, A., et al. Chronic inhibition of the Na+/H+ - exchanger causes regression of hypertrophy, heart failure, and ionic and electrophysiological remodelling. British journal of pharmacology 154, 1266-1275 (2008).
97. Baartscheer, A., et al. Increased Na+/H+-exchange activity is the cause of increased [Na+]i and underlies disturbed calcium handling in the rabbit pressure and volume overload heart failure model. Cardiovascular research 57, 1015-1024 (2003).
98. Verdonck, F., Volders, P.G., Vos, M.A. & Sipido, K.R. Intracellular Na+ and altered Na+ transport mechanisms in cardiac hypertrophy and failure. Journal of molecular and cellular cardiology 35, 5-25 (2003).
99. Hobai, I.A. & O'Rourke, B. The potential of Na+/Ca2+ exchange blockers in the treatment of cardiac disease. Expert opinion on investigational drugs 13, 653-664(2004).
100.Catterall, W.A. & Coppersmith, J. Pharmacological properties of sodium channels in cultured rat heart cells. Molecular pharmacology 20, 533-542 (1981).
101. Amy, C. & Kirshner, N. 22Na+ uptake and catecholamine secretion by primary cultures of adrenal medulla cells. Journal of neurochemistry 39, 132-142 (1982).
102. Fleckenstein, A., Janke, J., Doring, H.J. & Leder, O. Myocardial fiber necrosis due to intracellular Ca overload-a new principle in cardiac pathophysiology. Recent advances in studies on cardiac structure and metabolism 4, 563-580 (1974).
103.Leonard, J.P. & Salpeter, M.M. Agonist-induced myopathy at the neuromuscular junction is mediated by calcium. The Journal of cell biology 82, 811-819 (1979).
104.Schanne, F.A., Kane, A.B., Young, E.E. & Farber, J.L. Calcium dependence of toxic cell death: a final common pathway. Science (New York, N.Y206, 700-702 (1979).
105.Trump,B.F.& Berezesky,I.K.Calcium-mediated cell injury and cell death.Faseb J 9,219-228 (1995).
106.Ferri,K.F.& Kroemer,G.Organelle-specific initiation of cell death pathways.Nature cell biology 3,E255-263 (2001).
107.Wagner,S.,et al.Ca2+/calmodulin-dependent protein kinase Ⅱ regulates cardiac Na+ channels.The Journal of clinical investigation 116,3127-3138 (2006).
1.Harding, H.P., Calfon, ML, Urano, F., Novoa, I. & Ron, D. Transcriptional and translational control in the Mammalian unfolded protein response. Annual review of cell and developmental biology 18, 575-599 (2002).
2. Kaufman, R.J. Orchestrating the unfolded protein response in health and disease. The Journal of clinical investigation 110, 1389-1398 (2002).
3.Mori, K. Tripartite management of unfolded proteins in the endoplasmic reticulum. Cell 101, 451-454 (2000).
4.Schroder, M. & Kaufman, R.J. ER stress and the unfolded protein response. Mutation research 569, 29-63 (2005).
5.Gaut, J.R. & Hendershot, L.M. The modification and assembly of proteins in the endoplasmic reticulum. Current opinion in cell biology 5, 589-595 (1993).
6. Brostrom, M.A., Prostko, C.R., Gmitter, D. & Brostrom, CO. Independent signaling of grp78 gene transcription and phosphorylation of eukaryotic initiator factor 2 alpha by the stressed endoplasmic reticulum. The Journal of biological chemistry 270,4127-4132 (1995).
7.Fernandez, F., Jannatipour, M., Hellman, U., Rokeach, L.A. & Parodi, A.J. A new stress protein: synthesis of Schizosaccharomyces pombe UDP--Glc:glycoprotein glucosyltransferase mRNA is induced by stress conditions but the enzyme is not essential for cell viability. The EMBO journal 15, 705-713 (1996).
8.Dorner, A.J., et al. The stress response in Chinese hamster ovary cells. Regulation of ERp72 and protein disulfide isomerase expression and secretion. The Journal of biological chemistiy 265, 22029-22034 (1990).
9.Takatsuki, A., Arima, K. & Tamura, G Tunicamycin, a new antibiotic.Ⅰ. Isolation and characterization of tunicamycin. The Journal of antibiotics 24, 215-223 (1971).
10.Lin, H.Y., et al. The 170-kDa glucose-regulated stress protein is an endoplasmic reticulum protein that binds immunoglobulin. Molecular biology of the cell 4, 1109-1119(1993).
11. Price, B.D., Mannheim-Rodman, L.A. & Calderwood, S.K. Brefeldin A, thapsigargin, and AIF4- stimulate the accumulation of GRP78 mRNA in a cycloheximide dependent manner, whilst induction by hypoxia is independent of protein synthesis. Journal of cellular physiology 152, 545-552 (1992).
12. Schroder, M. & Kaufman, R.J. The mammalian unfolded protein response. Annual review of biochemistry 74, 739-789 (2005).
13. Shi, Y., et al. Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control. Molecular and cellular biology 18, 7499-7509 (1998).
14. Harding, H.P., Zhang, Y. & Ron, D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 397, 271-274 (1999).
15. Harding, H.P., Zhang, Y, Bertolotti, A., Zeng, H. & Ron, D. Perk is essential for translational regulation and cell survival during the unfolded protein response. Molecular cell 5, 897-904 (2000).
16. Harding, H.P., et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Molecular cell 11, 619-633 (2003).
17. Iwawaki, T., et al. Translational control by the ER transmembrane kinase/ribonuclease IRE1 under ER stress. Nature cell biology 3, 158-164 (2001).
18. Tirasophon, W., Welihinda, A.A. & Kaufman, R.J. A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells. Genes & development 12, 1812-1824(1998).
19. Wang, X.Z., et al. Cloning of mammalian Ire1 reveals diversity in the ER stress responses. The EMBO journal 17, 5708-5717 (1998).
20. Bertolotti, A., Zhang, Y, Hendershot, L.M., Harding, H.P. & Ron, D. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nature cell biology 2, 326-332 (2000).
21. Yoshida, H., Matsui, T., Yamamoto, A., Okada, T. & Mori, K. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107, 881-891 (2001).
22. Lee, A.H., Iwakoshi, N.N. & Glimcher, L.H. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Molecular and cellular biology 23, 7448-7459 (2003).
23. Yan, W., et al. Control of PERK eIF2alpha kinase activity by the endoplasmic reticulum stress-induced molecular chaperone P58IPK. Proceedings of the National Academy of Sciences of the United States of America 99, 15920-15925 (2002).
24. Ladiges, W.C., et al. Pancreatic beta-cell failure and diabetes in mice with a deletion mutation of the endoplasmic reticulum molecular chaperone gene P58IPK. Diabetes 54, 1074-1081 (2005).
25. van Huizen, R., Martindale, J.L., Gorospe, M. & Holbrook, N.J. P58IPK, a novel endoplasmic reticulum stress-inducible protein and potential negative regulator of eIF2alpha signaling. The Journal of biological chemistry 278, 15558-15564 (2003).
26. Nishitoh, H., et al. ASK1 is essential for JNK/SAPK activation by TRAF2. Molecular cell 2, 389-395(1998).
27. Hatai, T., et al. Execution of apoptosis signal-regulating kinase 1 (ASK1)-induced apoptosis by the mitochondria-dependent caspase activation. The Journal of biological chemistry 275, 26576-26581 (2000).
28. Nishitoh, H., et al. ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes &development 16, 1345-1355 (2002).
29. Urano, F., et al. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science (New York, N.Y 287, 664-666 (2000).
30. Davis, R.J. Signal transduction by the JNK group of MAP kinases. Cell 103, 239-252(2000).
31. Oono, K., et al. JAB1 participates in unfolded protein responses by association and dissociation with IRE1. Neurochemistry international 45, 765-772 (2004).
32. Yoneda, T., et al. Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress. The Journal of biological chemistry 276,13935-13940(2001).
33. Zinszner, H., et al. CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes & development 12, 982-995(1998).
34. Brush, M.H., Weiser, D.C. & Shenolikar, S. Growth arrest and DNA damage-inducible protein GADD34 targets protein phosphatase 1 alpha to the endoplasmic reticulum and promotes dephosphorylation of the alpha subunit of eukaryotic translation initiation factor 2. Molecular and cellular biology 23, 1292-1303 (2003).
35. Adler, H.T., et al. Leukemic HRX fusion proteins inhibit GADD34-induced apoptosis and associate with the GADD34 and hSNF5/INI1 proteins. Molecular and cellular biology 19, 7050-7060 (1999).
36. Boyce, M., et al. A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress. Science (New York, N.Y 307, 935-939 (2005).
37. Marciniak, S.J., et al. CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum.Genes & development 18,3066-3077 (2004).
38.Ohoka,N.,Yoshii,S.,Hattori,T.,Onozaki,K.& Hayashi,H.TRB3,a novel ER stress-inducible gene,is induced via ATF4-CHOP pathway and is involved in cell death.The EMBO journal 24,1243-1255 (2005).
39.Du,K.,Herzig,S.,Kulkarni,R.N.& Montminy,M.TRB3:a tribbles homolog that inhibits Akt/PKB activation by insulin in liver.Science (New York,N.Y300,1574-1577 (2003).
40.Hu,P.,Han,Z.,Couvil]on,A.D.&Exton,J.H.Critical role of endogenous Akt/IAPs and MEK1/ERK pathways in counteracting endoplasmic reticulum stress-induced cell death.The Journal of biological chemistry 279,49420-49429 (2004).
41.Distelhorst,C.W.& McCormick,T.S.Bcl-2 acts subsequent to and independent of Ca2+ fluxes to inhibit apoptosis in thapsigargin- and glucocorticoid-treated mouse lymphoma cells.Cell calcium 19,473-483 (1996).
42.Wei,M.C.,et al.Proapoptotic BAX and BAK:a requisite gateway to mitochondrial dysfunction and death.Science (New York,N.Y 292,727-730 (2001).
43.Boya,P.,Cohen,I.,Zamzami,N.,Vieira,H.L.& Kroemer,G.Endoplasmic reticulum stress-induced cell death requires mitochondrial membrane permeabilization.Cell death and differentiation 9,465-467 (2002).
44.Hacki,J.,et al.Apoptotic crosstalk between the endoplasmic reticulum and mitochondria controlled by Bcl-2.Oncogene 19,2286-2295 (2000).
45.Matsumoto,M.,Minami,M.,Takeda,K.,Sakao,Y.& Akira,S.Ectopic expression of CHOP (GADD 153) induces apoptosis in M1 myeloblastic leukemia cells.FEBS letters 395,143-147 (1996).
46.McCullough,K.D.,Martindale,J.L.,Klotz,L.O.,Aw,T.Y.& Holbrook,N.J.Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state.Molecular and cellular biology 21,1249-1259 (2001).
47.Bassik,M.C.,Scorrano,L.,Oakes,S.A.,Pozzan,T.& Korsmeyer,S.J.Phosphorylation of BCL-2 regulates ER Ca2+ homeostasis and apoptosis.The EMBO journal 23,1207-1216 (2004).
48.Lei,K.& Davis,R.J.JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis.Proceedings of the National Academy of Sciences of the United States of America 100,2432-2437 (2003).
49. Morishima, N., Nakanishi, K., Tsuchiya, K., Shibata, T. & Seiwa, E. Translocation of Bim to the endoplasmic reticulum (ER) mediates ER stress signaling for activation of caspase-12 during ER stress-induced apoptosis. The Journal of biological chemistry 279,50375-50381 (2004).
50. Hetz, C, et al. Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1 alpha. Science (New York, N.Y312, 572-576 (2006).
51. Li, J., Lee, B. & Lee, A.S. Endoplasmic reticulum stress-induced apoptosis: multiple pathways and activation of p53-up-regulated modulator of apoptosis (PUMA) and NOXA by p53. The Journal of biological chemistry 281, 7260-7270 (2006).
52. Szegezdi, E., Fitzgerald, U. & Samali, A. Caspase-12 and ER-stress-mediated apoptosis: the story so far. Annals of the New York Academy of Sciences 1010, 186-194(2003).
53. Nakagawa, T., et al Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 403, 98-103 (2000).
54. Saleh, M., et al. Enhanced bacterial clearance and sepsis resistance in caspase-12-deficient mice. Nature 440, 1064-1068 (2006).
55. Austin, R.C., Lentz, S.R. & Werstuck, G.H. Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease. Cell death and differentiation 11 Suppl 1, S56-64 (2004).
56. Lawrence de Koning, A.B., Werstuck, G.H., Zhou, J. & Austin, R.C. Hyperhomocysteinemia and its role in the development of atherosclerosis. Clinical biochemistry 36, 431-441 (2003).
57. Outinen, P.A., et al. Homocysteine-induced endoplasmic reticulum stress and growth arrest leads to specific changes in gene expression in human vascular endothelial cells. Blood 94, 959-967(1999).
58. Huang, R.F., Huang, S.M., Lin, B.S., Wei, J.S. & Liu, T.Z. Homocysteine thiolactone induces apoptotic DNA damage mediated by increased intracellular hydrogen peroxide and caspase 3 activation in HL-60 cells. Life sciences 68, 2799-2811 (2001).
59. Zhang, C., et al. Homocysteine induces programmed cell death in human vascular endothelial cells through activation of the unfolded protein response. The Journal of biological chemistry 276, 35867-35874 (2001).
60. Zhou, J., et al. Dietary supplementation with methionine and homocysteine promotes early atherosclerosis but not plaque rupture in ApoE-deficient mice. Arteriosclerosis, thrombosis, and vascular biology 21, 1470-1476 (2001).
61. Hofmann, M.A., et al. Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model. The Journal of clinical investigation 107,675-683(2001).
62. Werstuck, G.H., et al Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways. The Journal of clinical investigation 107, 1263-1273 (2001).
63. Devries-Seimon, T., et al. Cholesterol-induced macrophage apoptosis requires ER stress pathways and engagement of the type A scavenger receptor. The Journal of cell biology 171, 61-73(2005).
64. Feng, B., et al. The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages. Nature cell biology 5, 781-792 (2003).
65. Han, S., et al. Macrophage insulin receptor deficiency increases ER stress-induced apoptosis and necrotic core formation in advanced atherosclerotic lesions. Cell metabolism 3, 257-266 (2006).
66. Majors, A.K., et al. Endoplasmic reticulum stress induces hyaluronan deposition and leukocyte adhesion. The Journal of biological chemistry 278, 47223-47231 (2003).
67. Little, E., Tocco, G, Baudry, M., Lee, A.S. & Schreiber, S.S. Induction of glucose-regulated protein (glucose-regulated protein 78/BiP and glucose-regulated protein 94) and heat shock protein 70 transcripts in the immature rat brain following status epilepticus. Neuroscience 75, 209-219 (1996).
68. DeGracia, D.J., Kumar, R., Owen, C.R., Krause, G.S. & White, B.C. Molecular pathways of protein synthesis inhibition during brain reperfusion: implications for neuronal survival or death. J Cereb Blood Flow Metab 22, 127-141 (2002).
69. Rissanen, A., Sivenius, J. & Jolkkonen, J. Prolonged bihemispheric alterations in unfolded protein response related gene expression after experimental stroke. Brain Res 1087, 60-66 (2006).
70. Tajiri, S., et al. Ischemia-induced neuronal cell death is mediated by the endoplasmic reticulum stress pathway involving CHOP. Cell death and differentiation 11, 403-415(2004).
71. Kumar, R., et al. Brain ischemia and reperfusion activates the eukaryotic initiation factor 2alpha kinase, PERK. Journal of neurochemistry 77, 1418-1421 (2001).
72. Paschen, W., Gissel, C., Linden, T., Althausen, S. & Doutheil, J. Activation of gadd153 expression through transient cerebral ischemia: evidence that ischemia causes endoplasmic reticulum dysfunction. Brain research 60, 115-122 (1998).
73. Azfer, A., Niu, J., Rogers, L.M., Adamski, F.M. & Kolattukudy, RE. Activation of endoplasmic reticulum stress response during the development of ischemic heart disease. American journal of physiology 291, H1411-1420 (2006).
74. Szegezdi, E., et al. ER stress contributes to ischemia-induced cardiomyocyte apoptosis.Biochemical and biophysical research communications 349, 1406-1411 (2006).
75. Kuznetsov, G., Bush, K.T., Zhang, P.L. & Nigam, S.K. Perturbations in maturation of secretory proteins and their association with endoplasmic reticulum chaperones in a cell culture model for epithelial ischemia. Proceedings of the National Academy of Sciences of the United States of America 93, 8584-8589 (1996).
76. Kohno, K., et al. Neuroprotective nitric oxide synthase inhibitor reduces intracellular calcium accumulation following transient global ischemia in the gerbil. Neuroscience letters 224, 17-20(1997).
77. Iadecola, C., Zhang, F., Casey, R., Nagayama, M. & Ross, M.E. Delayed reduction of ischemic brain injury and neurological deficits in mice lacking the inducible nitric oxide synthase gene. J Neurosci 17, 9157-9164 (1997).
78. Thuerauf, D.J., et al. Sarco/endoplasmic reticulum calcium ATPase-2 expression is regulated by ATF6 during the endoplasmic reticulum stress response: intracellular signaling of calcium stress in a cardiac myocyte model system. The Journal of biological chemistry 276, 48309-48317 (2001).
79. Zhang, P.L., et al. Preinduced molecular chaperones in the endoplasmic reticulum protect cardiomyocytes from lethal injury. Annals of clinical and laboratory science 34,449-457 (2004).
80. Araki, E., Oyadomari, S. & Mori, M. Endoplasmic reticulum stress and diabetes mellitus. Internal medicine (Tokyo, Japan) 42, 7-14 (2003).
81. Harding, H.P. & Ron, D. Endoplasmic reticulum stress and the development of diabetes: a review. Diabetes 51 Suppl 3, S455-461 (2002).
82. Oyadomari, S., Araki, E. & Mori, M. Endoplasmic reticulum stress-mediated apoptosis in pancreatic beta-cells. Apoptosis 7, 335-345 (2002).
83. Delepine, M., et al. EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome. Nature genetics 25, 406-409 (2000).
84. Harding, H.P., et al. Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice reveals a role for translational control in secretory cell survival. Molecular cell 7,1153-1163(2001).
85. Zhang, P., et al. The PERK eukaryotic initiation factor 2 alpha kinase is required for the development of the skeletal system, postnatal growth, and the function and viability of the pancreas. Molecular and cellular biologyl 22, 3864-3874 (2002).
86. Scheuner, D., et al. Translational control is required for the unfolded protein response and in vivo glucose homeostasis. Molecular cell 7,1165-1176 (2001).
87. Scheuner, D., et al. Control of mRNA translation preserves endoplasmic reticulum function in beta cells and maintains glucose homeostasis. Nature medicine 11, 757-764(2005).
88. Oyadomari, S., et al. Targeted disruption of the Chop gene delays endoplasmic reticulum stress-mediated diabetes. The Journal of clinical investigation 109, 525-532 (2002).
89. Allen, J.R., et al. High ER stress in beta-cells stimulates intracellular degradation of misfolded insulin. Biochemical and biophysical research communications 324,166-170(2004).
90. Nozaki, J., et al. The endoplasmic reticulum stress response is stimulated through the continuous activation of transcription factors ATF6 and XBP1 in Ins2+/Akita pancreatic beta cells. Genes Cells 9, 261-270 (2004).
91. Fonseca, S.G., et al. WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pancreatic beta-cells. The Journal of biological chemistry 280, 39609-39615 (2005).
92. Yamada, T., et al. WFS1-deficiency increases endoplasmic reticulum stress, impairs cell cycle progression and triggers the apoptotic pathway specifically in pancreatic beta-cells. Human molecular genetics 15, 1600-1609 (2006).
93. Ozcan, U., et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science (New York, N.Y 306, 457-461 (2004).
94. Nakatani, Y., et al. Involvement of endoplasmic reticulum stress in insulin resistance and diabetes. The Journal of biological chemistry 280, 847-851 (2005).
95. Thameem, F., Farook, V.S., Bogardus, C. & Prochazka, M. Association of amino acid variants in the activating transcription factor 6 gene (ATF6) on 1q21-q23 with type 2 diabetes in Pima Indians. Diabetes 55, 839-842 (2006).
96. Kerkela, R., et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nature medicine 12, 908-916 (2006).
97. Okada, K., et al. Prolonged endoplasmic reticulum stress in hypertrophic and failing heart after aortic constriction: possible contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis. Circulation 110, 705-712 (2004).
98. Hamada, H., et al. Dilated cardiomyopathy caused by aberrant endoplasmic reticulum quality control in mutant KDEL receptor transgenic mice. Molecular and cellular biology 24, 8007-8017 (2004).
99. Martindale, J.J., et al. Endoplasmic reticulum stress gene induction and protection from ischemia/reperfusion injury in the hearts of transgenic mice with a tamoxifen-regulated form of ATF6. Circulation research 98, 1186-1193 (2006).
100.Oyadomari, S. & Mori, M. Roles of CHOP/GADD153 in endoplasmic reticulum stress.Cell death and differentiation 11, 381-389 (2004).
101.Ito, Y., et al. Targeting of the c-Ab1 tyrosine kinase to mitochondria in endoplasmic reticulum stress-induced apoptosis. Molecular and cellular biology 21, 6233-6242(2001).
102.Chae, H.J., et al. BI-1 regulates an apoptosis pathway linked to endoplasmic reticulum stress. Molecular cell 15, 355-366 (2004).
2.Kaufman, R.J. Orchestrating the unfolded protein response in health and disease. The Journal of clinical investigation 110, 1389-1398 (2002).
3. Schroder, M. & Kaufman, R.J. ER stress and the unfolded protein response. Mutation research 569, 29-63 (2005).
4. Schroder, M. & Kaufman, R.J. The mammalian unfolded protein response. Annual review of biochemistry 74, 739-789 (2005).
5. Shi, Y., et al. Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control. Molecular and cellular biology 18, 7499-7509 (1998).
6.Harding, H.P., Zhang, Y. & Ron, D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 397, 271-274 (1999).
7.Iwawaki, T., et al. Translational control by the ER transmembrane kinase/ribonuclease IRE1 under ER stress. Nature cell biology 3, 158-164 (2001).
8.Tirasophon, W., Welihinda, A.A. & Kaufman, R.J. A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells. Genes & development 12,1812-1824(1998).
9. Wang, X.Z., et al. Cloning of mammalian Ire1 reveals diversity in the ER stress responses. The EMBO journal 17, 5708-5717 (1998).
10. Bertolotti, A., Zhang, Y., Hendershot, L.M., Harding, H.P. & Ron, D. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nature cell biology 2, 326-332 (2000).
11. Yoshida, H., Matsui, T., Yamamoto, A., Okada, T. & Mori, K. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107, 881-891 (2001).
12. Nishitoh, H., et al. ASK1 is essential for JNK/SAPK activation by TRAF2. Molecular cell 2, 389-395(1998).
13. Zinszner, H., et al. CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes & development 12, 982-995 (1998).
14. Distelhorst, C.W. & McCormick, T.S. Bcl-2 acts subsequent to and independent of Ca2+ fluxes to inhibit apoptosis in thapsigargin- and glucocorticoid-treated mouse lymphoma cells. Cell calcium 19, 473-483 (1996).
15. Wei, M.C., et al. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science (New York, N.Y292, 727-730 (2001).
16. Boya, P., Cohen, I., Zamzami, N., Vieira, H.L. & Kroemer, G. Endoplasmic reticulum stress-induced cell death requires mitochondrial membrane permeabilization. Cell death and differentiation 9, 465-467 (2002).
17. Hacki, J., et al. Apoptotic crosstalk between the endoplasmic reticulum and mitochondria controlled by Bcl-2. Oncogene 19, 2286-2295 (2000).
18. Bassik, M.C., Scorrano, L., Oakes, S.A., Pozzan, T. & Korsmeyer, S.J. Phosphorylation of BCL-2 regulates ER Ca2+ homeostasis and apoptosis. The EMBO journal 23, 1207-1216(2004).
19. Nakagawa, T., et al. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 403, 98-103 (2000).
20. Okada, K., et al Prolonged endoplasmic reticulum stress in hypertrophic and failing heart after aortic constriction: possible contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis. Circulation 110, 705-712 (2004).
21. Szegezdi, E., et al. ER stress contributes to ischemia-induced cardiomyocyte apoptosis. Biochemical and biophysical research communications 349, 1406-1411 (2006).
22. Myoishi, M., et al. Increased endoplasmic reticulum stress in atherosclerotic plaques associated with acute coronary syndrome. Circulation 116, 1226-1233 (2007).
23. Levy, D., et al. Long-term trends in the incidence of and survival with heart failure.The New England journal of medicine 347, 1397-1402 (2002).
24. Kerkela, R., et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nature medicine 12, 908-916 (2006).
25. Simonian, M.H. & Smith, J.A. Spectrophotometric and colorimetric determination of protein concentration. Current protocols in molecular biology / edited by Frederick M. Ausubel... [et al Chapter 10, Unit 10 11A (2006).
26. Yoshida, H., Haze, K., Yanagi, H., Yura, T. & Mori, K. Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins. Involvement of basic leucine zipper transcription factors. The Journal of biological chemistry 273, 33741-33749 (1998).
27.Marx, J. Cell biology. A stressful situation. Science (New York, N.Y 313, 1564-1566(2006).
28.Davis, R.J. Signal transduction by the JNK group of MAP kinases. Cell 103, 239-252(2000).
29.Greenberg, B. Treatment of heart failure: state of the art and prospectives. Journal of cardiovascular pharmacology 38 Suppl 2, S59-63 (2001).
30. Hasegawa, K.,Iwai-Kanai,E.&Sasayama,S.Neurohormonal regulation of myocardial cell apoptosis during the development of heart failure. Journal of cellular physiology 186, 11-18 (2001).
31.Paull,J.R. &Widdop,R.E.Persistent cardiovascular effects of chronic renin-angiotensin system inhibition following withdrawal in adult spontaneously hypertensive rats. Journal of hypertension 19, 1393-1402 (2001).
32.Molkentin, J.D. & Dorn, G.W., 2nd. Cytoplasmic signaling pathways that regulate cardiac hypertrophy. Annual review of physiology 63, 391-426 (2001).
33.Colucci, W.S. Molecular and cellular mechanisms of myocardial failure. The American journal of cardiology 80, 15L-25L (1997).
34.Givertz, M.M. & Colucci, W.S. New targets for heart-failure therapy: endothelin, inflammatory cytokines, and oxidative stress. Lancet 352 Suppl 1, SI34-38 (1998).
35.Yoshida, H. ER stress and diseases. The FEBS journal 274, 630-658 (2007).
36.Austin, R.C., Lentz, S.R. & Werstuck, G.H. Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease. Cell death and differentiation 11 Suppl 1, S56-64 (2004).
37.Lawrence de Koning, A.B., Werstuck, G.H., Zhou, J. & Austin, R.C Hyperhomocysteinemia and its role in the elopment of atherosclerosis. Clinical biochemistry 36, 431 -441 (2003).
38. Outinen, P.A., et al. Homocysteine-induced endoplasmic reticulum stress and growth arrest leads to specific changes in gene expression in human vascular endothelial cells. Blood 94, 959-967(1999).
39. Huang, R.F., Huang, S.M., Lin, B.S., Wei, J.S. & Liu, T.Z. Homocysteine thiolactone induces apoptotic DNA damage mediated by increased intracellular hydrogen peroxide and caspase 3 activation in HL-60 cells. Life sciences 68, 2799-2811 (2001).
40.Zhang, C., et al. Homocysteine induces programmed cell death in human vascular endothelial cells through activation of the unfolded protein response. The Journal of biological chemistry 276, 35867-35874 (2001).
41. Zhou, J., et al. Dietary supplementation with methionine and homocysteine promotes early atherosclerosis but not plaque rupture in ApoE-deficient mice. Arteriosclerosis, thrombosis, and vascular biology 21, 1470-1476 (2001).
42. Hofmann, M.A., et al. Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model. The Journal of clinical investigation 107,675-683(2001).
43. Devries-Seimon, T., et al. Cholesterol-induced macrophage apoptosis requires ER stress pathways and engagement of the type A scavenger receptor. The Journal of cell biology 171, 61-73(2005).
44. Feng, B., et al. The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages. Nature cell biology 5, 781-792 (2003).
45. Han, S., et al. Macrophage insulin receptor deficiency increases ER stress-induced apoptosis and necrotic core formation in advanced atherosclerotic lesions. Cell metabolism 3, 257-266 (2006).
46. Majors, A.K., et al. Endoplasmic reticulum stress induces hyaluronan deposition and leukocyte adhesion. The Journal of biological chemistry 278, 47223-47231 (2003).
47. Yamamoto, K., et al. The KDEL receptor modulates the endoplasmic reticulum stress response through mitogen-activated protein kinase signaling cascades. The Journal of biological chemistry 278, 34525-34532 (2003).
48. Hamada, H., et al. Dilated cardiomyopathy caused by aberrant endoplasmic reticulum quality control in mutant KDEL receptor transgenic mice. Molecular and cellular biology 24, 8007-8017 (2004).
49. Frey, N. & Olson, E.N. Cardiac hypertrophy: the good, the bad, and the ugly. Annual review of physiology 65, 45-79 (2003).
50. Frey, N., Katus, H.A., Olson, E.N. & Hill, J.A. Hypertrophy of the heart: a new therapeutic target? Circulation 109, 1580-1589 (2004).
51. Eichhorn, E.J. & Bristow, M.R. Medical therapy can improve the biological properties of the chronically failing heart. A new era in the treatment of heart failure. Circulation 94,2285-2296(1996).
52. Massie, B.M. 15 years of heart-failure trials: what have we learned? Lancet 352 Suppl 1, SI29-33 (1998).
53. Bristow, M.R. Why does the myocardium fail? Insights from basic science. Lancet 352 Suppl 1, SI8-14 (1998).
54. Consensus recommendations for the management of chronic heart failure. On behalf of the membership of the advisory council to improve outcomes nationwide in heart failure. The American journal of cardiology S3, 1A-38A (1999).
55. Bristow, M.R. & Gilbert, E.M. Improvement in cardiac myocyte function by biological effects of medical therapy: a new concept in the treatment of heart failure. European heart journal 16 Suppl F, 20-31 (1995).
56. Marano, G., Palazzesi, S., Fadda, A., Vergari, A. & Ferrari, A.U. Attenuation of aortic banding-induced cardiac hypertrophy by propranolol is independent of beta-adrenoceptor blockade. Journal of hypertension 20, 763-769 (2002).
57. Oelze, M., et al. Nebivolol inhibits superoxide formation by NADPH oxidase and endothelial dysfunction in angiotensin Ⅱ-treated rats. Hypertension 48, 677-684(2006).
58. Nirmala, C. & Puvanakrishnan, R. Protective role of curcumin against isoproterenol induced myocardial infarction in rats. Molecular and cellular biochemistry 159, 85-93(1996).
59. Shioura, K.M., Geenen, D.L. & Goldspink, P.H. Assessment of cardiac function with the pressure-volume conductance system following myocardial infarction in mice. American journal of physiology 293, H2870-2877 (2007).
60. Samsamshariat, S.A., Hashemzadeh, M., Samsamshariat, Z. & Movahed, M.R. Cardiovascular and hemodynamic effect of polyethylene glycol in rats. Cardiovasc Revasc Med 6, 70-72 (2005).
61. Pacher, P., et al. Left ventricular pressure-volume relationship in a rat model of advanced aging-associated heart failure. American journal of physiology 287, H2132-2137 (2004).
62. Rao, R.V., et al. Coupling endoplasmic reticulum stress to the cell death program: role of the ER chaperone GRP78. FEBS letters 514, 122-128 (2002).
63. Xu, C., Bailly-Maitre, B. & Reed, J.C. Endoplasmic reticulum stress: cell life and death decisions. The Journal of clinical investigation 115, 2656-2664 (2005).
64. Lee, A.H., Iwakoshi, N.N. & Glimcher, L.H. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Molecular and cellular biology 23, 7448-7459 (2003).
65. Yan, W., et al. Control of PERK eIF2alpha kinase activity by the endoplasmic reticulum stress-induced molecular chaperone P58IPK. Proceedings of the National Academy of Sciences of the United States of America 99, 15920-15925 (2002).
66. Hatai, T., et al. Execution of apoptosis signal-regulating kinase 1 (ASK1)-induced apoptosis by the mitochondria-dependent caspase activation. The Journal of biological chemistry 275, 26576-26581 (2000).
67. Nishitoh, H., et al. ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes & development 16, 1345-1355 (2002).
68. Urano, F., et al. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science (New York, N. Y 287, 664-666 (2000).
69. Zhu, W.Z., et al. Linkage of beta1-adrenergic stimulation to apoptotic heart cell death through protein kinase A-independent activation of Ca2+/calmodulin kinase Ⅱ. The Journal of clinical investigation 111, 617-625 (2003).
70. Wang, W., et al. Sustained betal-adrenergic stimulation modulates cardiac contractility by Ca2+/calmodulin kinase signaling pathway. Circulation research 95, 798-806 (2004).
71. Abraham, W.T. Switching between beta blockers in heart failure patients: rationale and practical considerations. Congestive heart failure (Greenwich, Conn 9, 271-278(2003).
72. Communal, C., Singh, K., Pimentel, D.R. & Colucci, W.S. Norepinephrine stimulates apoptosis in adult rat ventricular myocytes by activation of the beta-adrenergic pathway. Circulation 98, 1329-1334 (1998).
73. Iwai-Kanai, E., et al. alpha- and beta-adrenergic pathways differentially regulate cell type-specific apoptosis in rat cardiac myocytes. Circulation 100, 305-311 (1999).
74. Zheng, M., Han, Q.D. & Xiao, R.P. Distinct beta-adrenergic receptor subtype signaling in the heart and their pathophysiological relevance. Sheng Li Xue Bao 56, 1-15(2004).
75. Saraste, A., et al. Apoptosis in human acute myocardial infarction. Circulation 95, 320-323 (1997).
76. Zhu, W.Z., et al. Dual modulation of cell survival and cell death by beta(2)-adrenergic signaling in adult mouse cardiac myocytes. Proceedings of the National Academy of Sciences of the United States of America 98, 1607-1612 (2001).
77. Lohse, M.J., Engelhardt, S. & Eschenhagen, T. What is the role of beta-adrenergic signaling in heart failure? Circulation research 93, 896-906 (2003).
78. Saito, S., et al. beta-Adrenergic pathway induces apoptosis through calcineurin activation in cardiac myocytes. The Journal of biological chemistry 275, 34528-34533(2000).
79. Matsuda, J.J., Lee, H. & Shibata, E.F. Enhancement of rabbit cardiac sodium channels by beta-adrenergic stimulation. Circulation research 70, 199-207 (1992).
80. Ono, K., Fozzard, H.A. & Hanck, D.A. Mechanism of cAMP-dependent modulation of cardiac sodium channel current kinetics. Circulation research 72, 807-815 (1993).
81. Moorman, J.R., Kirsch, G.E., Lacerda, A.E. & Brown, A.M. Angiotensin Ⅱ modulates cardiac Na+ channels in neonatal rat. Circulation research 65, 1804-1809 (1989).
82. Abraham, W.T., et al. Cardiac resynchronization in chronic heart failure. The New England journal of medicine 346, 1845-1853 (2002).
83. Mankad, S.,et al. Combined angiotensin Ⅱ receptor antagonism and angiotensin-converting enzyme inhibition further attenuates postinfarction left ventricular remodeling. Circulation 103, 2845-2850 (2001).
84. Orrenius, S., Zhivotovsky, B. & Nicotera, P. Regulation of cell death: the calcium-apoptosis link. Nat Rev Mol Cell Biol 4, 552-565 (2003).
85. Kent, R.L., Hoober, J.K. & Cooper, G.t. Load responsiveness of protein synthesis in adult mammalian myocardium: role of cardiac deformation linked to sodium influx. Circulation research 64, 74-85 (1989).
86. Kent, R.L., Mann, D.L. & Cooper, G.t. Signals for cardiac muscle hypertrophy in hypertension. Journal of cardiovascular pharmacology 17 Suppl 2, S7-13 (1991).
87. Yaoita, H., Sakabe, A., Maehara, K. & Maruyama, Y. Different effects of carvedilol, metoprolol, and propranolol on left ventricular remodeling after coronary stenosis or after permanent coronary occlusion in rats. Circulation 105, 975-980 (2002).
88. Laird, J.M., Carter, A.J., Grauert, M. & Cervero, F. Analgesic activity of a novel use-dependent sodium channel blocker, crobenetine, in mono-arthritic rats. British journal of pharmacology 134, 1742-1748 (2001).
89. Despa, S., Islam, M.A., Weber, C.R., Pogwizd, S.M. & Bers, D.M. Intracellular Na(+) concentration is elevated in heart failure but Na/K pump function is unchanged. Circulation 105, 2543-2548 (2002).
90. Baartscheer, A. & van Borren, M.M. Sodium ion transporters as new therapeutic targets in heart failure. Cardiovascular & hematological agents in medicinal chemistry 6, 229-236 (2008).
91. Nakamura, T.Y., Iwata, Y., Arai, Y., Komamura, K. & Wakabayashi, S. Activation of Na+/H+ exchanger 1 is sufficient to generate Ca2+ signals that induce cardiac hypertrophy and heart failure. Circulation research 103, 891-899 (2008).
92. Baartscheer, A. Chronic inhibition of na(+)/h(+)-exchanger in the heart. Current vascular pharmacology 4, 23-29 (2006).
93. Doggrell, S.A. & Hancox, J.C. Is timing everything? Therapeutic potential of modulators of cardiac Na(+) transporters. Expert opinion on investigational drugs 12, 1123-1142(2003).
94. Andersen, G.O., et al. Increased expression and function of the myocardial Na-K-2Cl cotransporter in failing rat hearts. Basic research in cardiology 101, 471-478 (2006).
95. Ramasamy, R., Payne, J.A., Whang, J., Bergmann, S.R. & Schaefer, S. Protection of ischemic myocardium in diabetics by inhibition of electroneutral Na+-K+-2C1-cotransporter. American journal of physiology 281, H515-522 (2001).
96. Baartscheer, A., et al. Chronic inhibition of the Na+/H+ - exchanger causes regression of hypertrophy, heart failure, and ionic and electrophysiological remodelling. British journal of pharmacology 154, 1266-1275 (2008).
97. Baartscheer, A., et al. Increased Na+/H+-exchange activity is the cause of increased [Na+]i and underlies disturbed calcium handling in the rabbit pressure and volume overload heart failure model. Cardiovascular research 57, 1015-1024 (2003).
98. Verdonck, F., Volders, P.G., Vos, M.A. & Sipido, K.R. Intracellular Na+ and altered Na+ transport mechanisms in cardiac hypertrophy and failure. Journal of molecular and cellular cardiology 35, 5-25 (2003).
99. Hobai, I.A. & O'Rourke, B. The potential of Na+/Ca2+ exchange blockers in the treatment of cardiac disease. Expert opinion on investigational drugs 13, 653-664(2004).
100.Catterall, W.A. & Coppersmith, J. Pharmacological properties of sodium channels in cultured rat heart cells. Molecular pharmacology 20, 533-542 (1981).
101. Amy, C. & Kirshner, N. 22Na+ uptake and catecholamine secretion by primary cultures of adrenal medulla cells. Journal of neurochemistry 39, 132-142 (1982).
102. Fleckenstein, A., Janke, J., Doring, H.J. & Leder, O. Myocardial fiber necrosis due to intracellular Ca overload-a new principle in cardiac pathophysiology. Recent advances in studies on cardiac structure and metabolism 4, 563-580 (1974).
103.Leonard, J.P. & Salpeter, M.M. Agonist-induced myopathy at the neuromuscular junction is mediated by calcium. The Journal of cell biology 82, 811-819 (1979).
104.Schanne, F.A., Kane, A.B., Young, E.E. & Farber, J.L. Calcium dependence of toxic cell death: a final common pathway. Science (New York, N.Y206, 700-702 (1979).
105.Trump,B.F.& Berezesky,I.K.Calcium-mediated cell injury and cell death.Faseb J 9,219-228 (1995).
106.Ferri,K.F.& Kroemer,G.Organelle-specific initiation of cell death pathways.Nature cell biology 3,E255-263 (2001).
107.Wagner,S.,et al.Ca2+/calmodulin-dependent protein kinase Ⅱ regulates cardiac Na+ channels.The Journal of clinical investigation 116,3127-3138 (2006).
1.Harding, H.P., Calfon, ML, Urano, F., Novoa, I. & Ron, D. Transcriptional and translational control in the Mammalian unfolded protein response. Annual review of cell and developmental biology 18, 575-599 (2002).
2. Kaufman, R.J. Orchestrating the unfolded protein response in health and disease. The Journal of clinical investigation 110, 1389-1398 (2002).
3.Mori, K. Tripartite management of unfolded proteins in the endoplasmic reticulum. Cell 101, 451-454 (2000).
4.Schroder, M. & Kaufman, R.J. ER stress and the unfolded protein response. Mutation research 569, 29-63 (2005).
5.Gaut, J.R. & Hendershot, L.M. The modification and assembly of proteins in the endoplasmic reticulum. Current opinion in cell biology 5, 589-595 (1993).
6. Brostrom, M.A., Prostko, C.R., Gmitter, D. & Brostrom, CO. Independent signaling of grp78 gene transcription and phosphorylation of eukaryotic initiator factor 2 alpha by the stressed endoplasmic reticulum. The Journal of biological chemistry 270,4127-4132 (1995).
7.Fernandez, F., Jannatipour, M., Hellman, U., Rokeach, L.A. & Parodi, A.J. A new stress protein: synthesis of Schizosaccharomyces pombe UDP--Glc:glycoprotein glucosyltransferase mRNA is induced by stress conditions but the enzyme is not essential for cell viability. The EMBO journal 15, 705-713 (1996).
8.Dorner, A.J., et al. The stress response in Chinese hamster ovary cells. Regulation of ERp72 and protein disulfide isomerase expression and secretion. The Journal of biological chemistiy 265, 22029-22034 (1990).
9.Takatsuki, A., Arima, K. & Tamura, G Tunicamycin, a new antibiotic.Ⅰ. Isolation and characterization of tunicamycin. The Journal of antibiotics 24, 215-223 (1971).
10.Lin, H.Y., et al. The 170-kDa glucose-regulated stress protein is an endoplasmic reticulum protein that binds immunoglobulin. Molecular biology of the cell 4, 1109-1119(1993).
11. Price, B.D., Mannheim-Rodman, L.A. & Calderwood, S.K. Brefeldin A, thapsigargin, and AIF4- stimulate the accumulation of GRP78 mRNA in a cycloheximide dependent manner, whilst induction by hypoxia is independent of protein synthesis. Journal of cellular physiology 152, 545-552 (1992).
12. Schroder, M. & Kaufman, R.J. The mammalian unfolded protein response. Annual review of biochemistry 74, 739-789 (2005).
13. Shi, Y., et al. Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control. Molecular and cellular biology 18, 7499-7509 (1998).
14. Harding, H.P., Zhang, Y. & Ron, D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 397, 271-274 (1999).
15. Harding, H.P., Zhang, Y, Bertolotti, A., Zeng, H. & Ron, D. Perk is essential for translational regulation and cell survival during the unfolded protein response. Molecular cell 5, 897-904 (2000).
16. Harding, H.P., et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Molecular cell 11, 619-633 (2003).
17. Iwawaki, T., et al. Translational control by the ER transmembrane kinase/ribonuclease IRE1 under ER stress. Nature cell biology 3, 158-164 (2001).
18. Tirasophon, W., Welihinda, A.A. & Kaufman, R.J. A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells. Genes & development 12, 1812-1824(1998).
19. Wang, X.Z., et al. Cloning of mammalian Ire1 reveals diversity in the ER stress responses. The EMBO journal 17, 5708-5717 (1998).
20. Bertolotti, A., Zhang, Y, Hendershot, L.M., Harding, H.P. & Ron, D. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nature cell biology 2, 326-332 (2000).
21. Yoshida, H., Matsui, T., Yamamoto, A., Okada, T. & Mori, K. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107, 881-891 (2001).
22. Lee, A.H., Iwakoshi, N.N. & Glimcher, L.H. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Molecular and cellular biology 23, 7448-7459 (2003).
23. Yan, W., et al. Control of PERK eIF2alpha kinase activity by the endoplasmic reticulum stress-induced molecular chaperone P58IPK. Proceedings of the National Academy of Sciences of the United States of America 99, 15920-15925 (2002).
24. Ladiges, W.C., et al. Pancreatic beta-cell failure and diabetes in mice with a deletion mutation of the endoplasmic reticulum molecular chaperone gene P58IPK. Diabetes 54, 1074-1081 (2005).
25. van Huizen, R., Martindale, J.L., Gorospe, M. & Holbrook, N.J. P58IPK, a novel endoplasmic reticulum stress-inducible protein and potential negative regulator of eIF2alpha signaling. The Journal of biological chemistry 278, 15558-15564 (2003).
26. Nishitoh, H., et al. ASK1 is essential for JNK/SAPK activation by TRAF2. Molecular cell 2, 389-395(1998).
27. Hatai, T., et al. Execution of apoptosis signal-regulating kinase 1 (ASK1)-induced apoptosis by the mitochondria-dependent caspase activation. The Journal of biological chemistry 275, 26576-26581 (2000).
28. Nishitoh, H., et al. ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes &development 16, 1345-1355 (2002).
29. Urano, F., et al. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science (New York, N.Y 287, 664-666 (2000).
30. Davis, R.J. Signal transduction by the JNK group of MAP kinases. Cell 103, 239-252(2000).
31. Oono, K., et al. JAB1 participates in unfolded protein responses by association and dissociation with IRE1. Neurochemistry international 45, 765-772 (2004).
32. Yoneda, T., et al. Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress. The Journal of biological chemistry 276,13935-13940(2001).
33. Zinszner, H., et al. CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes & development 12, 982-995(1998).
34. Brush, M.H., Weiser, D.C. & Shenolikar, S. Growth arrest and DNA damage-inducible protein GADD34 targets protein phosphatase 1 alpha to the endoplasmic reticulum and promotes dephosphorylation of the alpha subunit of eukaryotic translation initiation factor 2. Molecular and cellular biology 23, 1292-1303 (2003).
35. Adler, H.T., et al. Leukemic HRX fusion proteins inhibit GADD34-induced apoptosis and associate with the GADD34 and hSNF5/INI1 proteins. Molecular and cellular biology 19, 7050-7060 (1999).
36. Boyce, M., et al. A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress. Science (New York, N.Y 307, 935-939 (2005).
37. Marciniak, S.J., et al. CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum.Genes & development 18,3066-3077 (2004).
38.Ohoka,N.,Yoshii,S.,Hattori,T.,Onozaki,K.& Hayashi,H.TRB3,a novel ER stress-inducible gene,is induced via ATF4-CHOP pathway and is involved in cell death.The EMBO journal 24,1243-1255 (2005).
39.Du,K.,Herzig,S.,Kulkarni,R.N.& Montminy,M.TRB3:a tribbles homolog that inhibits Akt/PKB activation by insulin in liver.Science (New York,N.Y300,1574-1577 (2003).
40.Hu,P.,Han,Z.,Couvil]on,A.D.&Exton,J.H.Critical role of endogenous Akt/IAPs and MEK1/ERK pathways in counteracting endoplasmic reticulum stress-induced cell death.The Journal of biological chemistry 279,49420-49429 (2004).
41.Distelhorst,C.W.& McCormick,T.S.Bcl-2 acts subsequent to and independent of Ca2+ fluxes to inhibit apoptosis in thapsigargin- and glucocorticoid-treated mouse lymphoma cells.Cell calcium 19,473-483 (1996).
42.Wei,M.C.,et al.Proapoptotic BAX and BAK:a requisite gateway to mitochondrial dysfunction and death.Science (New York,N.Y 292,727-730 (2001).
43.Boya,P.,Cohen,I.,Zamzami,N.,Vieira,H.L.& Kroemer,G.Endoplasmic reticulum stress-induced cell death requires mitochondrial membrane permeabilization.Cell death and differentiation 9,465-467 (2002).
44.Hacki,J.,et al.Apoptotic crosstalk between the endoplasmic reticulum and mitochondria controlled by Bcl-2.Oncogene 19,2286-2295 (2000).
45.Matsumoto,M.,Minami,M.,Takeda,K.,Sakao,Y.& Akira,S.Ectopic expression of CHOP (GADD 153) induces apoptosis in M1 myeloblastic leukemia cells.FEBS letters 395,143-147 (1996).
46.McCullough,K.D.,Martindale,J.L.,Klotz,L.O.,Aw,T.Y.& Holbrook,N.J.Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state.Molecular and cellular biology 21,1249-1259 (2001).
47.Bassik,M.C.,Scorrano,L.,Oakes,S.A.,Pozzan,T.& Korsmeyer,S.J.Phosphorylation of BCL-2 regulates ER Ca2+ homeostasis and apoptosis.The EMBO journal 23,1207-1216 (2004).
48.Lei,K.& Davis,R.J.JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis.Proceedings of the National Academy of Sciences of the United States of America 100,2432-2437 (2003).
49. Morishima, N., Nakanishi, K., Tsuchiya, K., Shibata, T. & Seiwa, E. Translocation of Bim to the endoplasmic reticulum (ER) mediates ER stress signaling for activation of caspase-12 during ER stress-induced apoptosis. The Journal of biological chemistry 279,50375-50381 (2004).
50. Hetz, C, et al. Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1 alpha. Science (New York, N.Y312, 572-576 (2006).
51. Li, J., Lee, B. & Lee, A.S. Endoplasmic reticulum stress-induced apoptosis: multiple pathways and activation of p53-up-regulated modulator of apoptosis (PUMA) and NOXA by p53. The Journal of biological chemistry 281, 7260-7270 (2006).
52. Szegezdi, E., Fitzgerald, U. & Samali, A. Caspase-12 and ER-stress-mediated apoptosis: the story so far. Annals of the New York Academy of Sciences 1010, 186-194(2003).
53. Nakagawa, T., et al Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 403, 98-103 (2000).
54. Saleh, M., et al. Enhanced bacterial clearance and sepsis resistance in caspase-12-deficient mice. Nature 440, 1064-1068 (2006).
55. Austin, R.C., Lentz, S.R. & Werstuck, G.H. Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease. Cell death and differentiation 11 Suppl 1, S56-64 (2004).
56. Lawrence de Koning, A.B., Werstuck, G.H., Zhou, J. & Austin, R.C. Hyperhomocysteinemia and its role in the development of atherosclerosis. Clinical biochemistry 36, 431-441 (2003).
57. Outinen, P.A., et al. Homocysteine-induced endoplasmic reticulum stress and growth arrest leads to specific changes in gene expression in human vascular endothelial cells. Blood 94, 959-967(1999).
58. Huang, R.F., Huang, S.M., Lin, B.S., Wei, J.S. & Liu, T.Z. Homocysteine thiolactone induces apoptotic DNA damage mediated by increased intracellular hydrogen peroxide and caspase 3 activation in HL-60 cells. Life sciences 68, 2799-2811 (2001).
59. Zhang, C., et al. Homocysteine induces programmed cell death in human vascular endothelial cells through activation of the unfolded protein response. The Journal of biological chemistry 276, 35867-35874 (2001).
60. Zhou, J., et al. Dietary supplementation with methionine and homocysteine promotes early atherosclerosis but not plaque rupture in ApoE-deficient mice. Arteriosclerosis, thrombosis, and vascular biology 21, 1470-1476 (2001).
61. Hofmann, M.A., et al. Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model. The Journal of clinical investigation 107,675-683(2001).
62. Werstuck, G.H., et al Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways. The Journal of clinical investigation 107, 1263-1273 (2001).
63. Devries-Seimon, T., et al. Cholesterol-induced macrophage apoptosis requires ER stress pathways and engagement of the type A scavenger receptor. The Journal of cell biology 171, 61-73(2005).
64. Feng, B., et al. The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages. Nature cell biology 5, 781-792 (2003).
65. Han, S., et al. Macrophage insulin receptor deficiency increases ER stress-induced apoptosis and necrotic core formation in advanced atherosclerotic lesions. Cell metabolism 3, 257-266 (2006).
66. Majors, A.K., et al. Endoplasmic reticulum stress induces hyaluronan deposition and leukocyte adhesion. The Journal of biological chemistry 278, 47223-47231 (2003).
67. Little, E., Tocco, G, Baudry, M., Lee, A.S. & Schreiber, S.S. Induction of glucose-regulated protein (glucose-regulated protein 78/BiP and glucose-regulated protein 94) and heat shock protein 70 transcripts in the immature rat brain following status epilepticus. Neuroscience 75, 209-219 (1996).
68. DeGracia, D.J., Kumar, R., Owen, C.R., Krause, G.S. & White, B.C. Molecular pathways of protein synthesis inhibition during brain reperfusion: implications for neuronal survival or death. J Cereb Blood Flow Metab 22, 127-141 (2002).
69. Rissanen, A., Sivenius, J. & Jolkkonen, J. Prolonged bihemispheric alterations in unfolded protein response related gene expression after experimental stroke. Brain Res 1087, 60-66 (2006).
70. Tajiri, S., et al. Ischemia-induced neuronal cell death is mediated by the endoplasmic reticulum stress pathway involving CHOP. Cell death and differentiation 11, 403-415(2004).
71. Kumar, R., et al. Brain ischemia and reperfusion activates the eukaryotic initiation factor 2alpha kinase, PERK. Journal of neurochemistry 77, 1418-1421 (2001).
72. Paschen, W., Gissel, C., Linden, T., Althausen, S. & Doutheil, J. Activation of gadd153 expression through transient cerebral ischemia: evidence that ischemia causes endoplasmic reticulum dysfunction. Brain research 60, 115-122 (1998).
73. Azfer, A., Niu, J., Rogers, L.M., Adamski, F.M. & Kolattukudy, RE. Activation of endoplasmic reticulum stress response during the development of ischemic heart disease. American journal of physiology 291, H1411-1420 (2006).
74. Szegezdi, E., et al. ER stress contributes to ischemia-induced cardiomyocyte apoptosis.Biochemical and biophysical research communications 349, 1406-1411 (2006).
75. Kuznetsov, G., Bush, K.T., Zhang, P.L. & Nigam, S.K. Perturbations in maturation of secretory proteins and their association with endoplasmic reticulum chaperones in a cell culture model for epithelial ischemia. Proceedings of the National Academy of Sciences of the United States of America 93, 8584-8589 (1996).
76. Kohno, K., et al. Neuroprotective nitric oxide synthase inhibitor reduces intracellular calcium accumulation following transient global ischemia in the gerbil. Neuroscience letters 224, 17-20(1997).
77. Iadecola, C., Zhang, F., Casey, R., Nagayama, M. & Ross, M.E. Delayed reduction of ischemic brain injury and neurological deficits in mice lacking the inducible nitric oxide synthase gene. J Neurosci 17, 9157-9164 (1997).
78. Thuerauf, D.J., et al. Sarco/endoplasmic reticulum calcium ATPase-2 expression is regulated by ATF6 during the endoplasmic reticulum stress response: intracellular signaling of calcium stress in a cardiac myocyte model system. The Journal of biological chemistry 276, 48309-48317 (2001).
79. Zhang, P.L., et al. Preinduced molecular chaperones in the endoplasmic reticulum protect cardiomyocytes from lethal injury. Annals of clinical and laboratory science 34,449-457 (2004).
80. Araki, E., Oyadomari, S. & Mori, M. Endoplasmic reticulum stress and diabetes mellitus. Internal medicine (Tokyo, Japan) 42, 7-14 (2003).
81. Harding, H.P. & Ron, D. Endoplasmic reticulum stress and the development of diabetes: a review. Diabetes 51 Suppl 3, S455-461 (2002).
82. Oyadomari, S., Araki, E. & Mori, M. Endoplasmic reticulum stress-mediated apoptosis in pancreatic beta-cells. Apoptosis 7, 335-345 (2002).
83. Delepine, M., et al. EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome. Nature genetics 25, 406-409 (2000).
84. Harding, H.P., et al. Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice reveals a role for translational control in secretory cell survival. Molecular cell 7,1153-1163(2001).
85. Zhang, P., et al. The PERK eukaryotic initiation factor 2 alpha kinase is required for the development of the skeletal system, postnatal growth, and the function and viability of the pancreas. Molecular and cellular biologyl 22, 3864-3874 (2002).
86. Scheuner, D., et al. Translational control is required for the unfolded protein response and in vivo glucose homeostasis. Molecular cell 7,1165-1176 (2001).
87. Scheuner, D., et al. Control of mRNA translation preserves endoplasmic reticulum function in beta cells and maintains glucose homeostasis. Nature medicine 11, 757-764(2005).
88. Oyadomari, S., et al. Targeted disruption of the Chop gene delays endoplasmic reticulum stress-mediated diabetes. The Journal of clinical investigation 109, 525-532 (2002).
89. Allen, J.R., et al. High ER stress in beta-cells stimulates intracellular degradation of misfolded insulin. Biochemical and biophysical research communications 324,166-170(2004).
90. Nozaki, J., et al. The endoplasmic reticulum stress response is stimulated through the continuous activation of transcription factors ATF6 and XBP1 in Ins2+/Akita pancreatic beta cells. Genes Cells 9, 261-270 (2004).
91. Fonseca, S.G., et al. WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pancreatic beta-cells. The Journal of biological chemistry 280, 39609-39615 (2005).
92. Yamada, T., et al. WFS1-deficiency increases endoplasmic reticulum stress, impairs cell cycle progression and triggers the apoptotic pathway specifically in pancreatic beta-cells. Human molecular genetics 15, 1600-1609 (2006).
93. Ozcan, U., et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science (New York, N.Y 306, 457-461 (2004).
94. Nakatani, Y., et al. Involvement of endoplasmic reticulum stress in insulin resistance and diabetes. The Journal of biological chemistry 280, 847-851 (2005).
95. Thameem, F., Farook, V.S., Bogardus, C. & Prochazka, M. Association of amino acid variants in the activating transcription factor 6 gene (ATF6) on 1q21-q23 with type 2 diabetes in Pima Indians. Diabetes 55, 839-842 (2006).
96. Kerkela, R., et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nature medicine 12, 908-916 (2006).
97. Okada, K., et al. Prolonged endoplasmic reticulum stress in hypertrophic and failing heart after aortic constriction: possible contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis. Circulation 110, 705-712 (2004).
98. Hamada, H., et al. Dilated cardiomyopathy caused by aberrant endoplasmic reticulum quality control in mutant KDEL receptor transgenic mice. Molecular and cellular biology 24, 8007-8017 (2004).
99. Martindale, J.J., et al. Endoplasmic reticulum stress gene induction and protection from ischemia/reperfusion injury in the hearts of transgenic mice with a tamoxifen-regulated form of ATF6. Circulation research 98, 1186-1193 (2006).
100.Oyadomari, S. & Mori, M. Roles of CHOP/GADD153 in endoplasmic reticulum stress.Cell death and differentiation 11, 381-389 (2004).
101.Ito, Y., et al. Targeting of the c-Ab1 tyrosine kinase to mitochondria in endoplasmic reticulum stress-induced apoptosis. Molecular and cellular biology 21, 6233-6242(2001).
102.Chae, H.J., et al. BI-1 regulates an apoptosis pathway linked to endoplasmic reticulum stress. Molecular cell 15, 355-366 (2004).