阿托伐他汀和过氧化氢抑制血管收缩的机理
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摘要
背景：动脉粥样硬化是一种最终导致血管壁变硬变厚的血管损伤，高血压是动脉粥样硬化的主要危险因素之一，而血管功能紊乱是诱发高血压的重要因素之一。
某些病理条件下，如氧化应激（oxidative stress），会促使血管平滑肌失去收缩能力，其本质是血管平滑肌细胞对血管活性物质失去正常的生理反应。长期的血管收缩功能丧失会致血管僵硬，对血压产生影响。我们的研究初步证实，过氧化氢（hydrogen peroxide，H_2O_2）能不可逆性的抑制血管收缩，导致血管僵硬；而雷帕霉素（Rapamycin，Rapa）可以减缓此过程的发生。
然而在另外一些情况，血管平滑肌对血管活性物质有比正常情况下更强的反应性，导致血管收缩过强，血管压力升高，亦对血压产生影响。我们的初步研究表明，他汀类降脂药物阿托伐他汀（Atorvastatin，ATV）通过抑制血管平滑肌细胞myocardin的表达来降低动脉血管收缩能力，证明ATV具有潜在的通过抑制血管收缩强度来调控血压的能力。
基于我们的初步研究结果，本论文主要包括两个独立的研究：ATV和H_2O_2各自抑制血管收缩的分子机理。
第一部分ATV通过抑制myocardin表达降低血管平滑肌收缩
目的：除了降血脂效应，他汀类（statins）药物的多效性被广泛关注，特别是其对心脑血管的保护作用，但机制尚不明确。在血管平滑肌细胞，他汀类药物可抑制RhoA-ROCK信号通路抑制平滑肌的功能。Myocardin是血清反应因子（SRF）的辅助因子，能上调平滑肌特异性收缩蛋白的表达，是平滑肌细胞分化的关键因子。RhoA-ROCK信号通路的激活可直接触发平滑肌收缩，同时也诱导myocardin基因的表达。因此我们研究他汀类药物的血管保护作用是否与抑制myocardin的表达有关。
方法与结果：C57小鼠腹腔内连续注射ATV（i.p.20mg/kg/天）5天后，分离心脏、胸主动脉及颈总动脉。蛋白质印迹法（Western blotting）检测myocardin及其下游平滑肌特异蛋白SM α-actin和SM22的表达；实时定量聚合酶链反应（Real-time PolymeRase chain reaction, RT-qPCR）检测myocardin及其下游靶基因SM α-actin和SM22mRNA表达。肌张力描计技术（Myography）检测去内皮的胸主动脉血管环对氯化钾（potassium chloride，KCl）、去氧肾上腺素（phenylephrine，PE）等血管活性物的反应。同时，Myography）检测未经ATV处理的C57小鼠胸主动脉血管环ATV（500μM）及ROCK抑制剂Y-27632（10μM）孵育90min前后对KCl和PE的反应。
小鼠及人的主动脉平滑肌细胞系（mSMCs和hSMCs），0%血清培养基饥饿24h后以KCl（60mM）处理细胞24h，RT-qPCR技术检测可知KCl刺激myocardin及其下游靶基因SM α-actin和SM22mRNA表达；这种刺激效应能被ATV（1μM，10μM）抑制。甲羟戊酸（Meva，300μM），香叶基香叶基焦磷酸酯（GGPP，1μM）可逆转ATV的抑制，而法尼基焦磷酸酯（FPP，1μM）不能。ROCK抑制剂Y-27632（10μM）可模拟ATV对myocardin及其下游靶基因SM α-actin和SM22mRNA表达的抑制效应，提示RhoA-ROCK通路与之有关。以Triton X-114萃取法、超速离心、Pull-down及Western blotting技术检测，ATV（100μM）处理的hSMCs的RhoA的法尼基化、胞膜转位及活化均明显降低，而Meva（300μM）可逆转该作用。
第二部分H_2O_2通过Rapa敏感机制诱导血管平滑肌收缩抑制
目的：氧化应激能使血管顺应性降低，在血管老化中扮演了重要角色。Rapa是哺乳动物雷帕霉素靶蛋白（the mammalian target of rapamycin，mTOR）特异性的抑制剂。而Rapa具有延长小鼠寿命、减缓衰老的作用。因此，我们通过Rapa研究H_2O_2对小鼠动脉血管收缩抑制的机理。
方法与结果：用Myography技术检测小鼠胸主动脉及肠系膜动脉（阻力血管）血管环暴露在H_2O_2（200μM）3h前后KCl（50mM）和PE（1μM）诱导收缩的变化。H_2O_2不可逆性的完全抑制血管环的收缩功能；若提前20min加入雷帕霉素（20μM），血管环的收缩能力被部分保留；蛋白合成抑制剂放线菌素D（Act D，1μM）和基因转录抑制剂环孢素（CHX，10μM）不具有保护作用；而钙调神经磷酸酶（calcineurin，CaN）的抑制剂环孢素A（CsA，1μM）和FK506（1μM）能模拟Rapa的保护作用。
蛋白印迹分析法（Western blotting）显示H_2O_2处理动脉环的mTORC1下游底物40s核糖体蛋白S6激酶（S6K）和真核细胞启动因子4E结合蛋白（4EBP1）的磷酸化未增加，提示H_2O_2对mTOR通路的激活未通过mTORC1，而可能与mTORC2有关。H_2O_2抑制的平滑肌肌球蛋白轻链20kD亚基（MLC20）的磷酸化，而该作用能被Rapa部分阻断。
CaN活性测定显示，H_2O_2能增加CaN的活化，该作用可被雷帕霉素所抑制。
结论：基于以上两方面的研究，我们认为：（1）ATV通过抑制myocardin的表达，降低血管平滑肌收缩能力；该机制与RhoA-ROCK通路有关。该研究提示ATV通过对血管收缩能力的抑制，可能成为他汀类药物治疗高血压的依据；（2）H_2O_2对血管收缩功能具有损伤作用，而Rapa对该损伤作用具有保护效应；其机制与mTOR通路的调节有关。该研究提示mTOR通路可能作为氧化损伤导致的血管收缩功能异常的治疗靶点。
The mechanisms underlying inhibitory effects of atorvastatin andhydrogen peroxide on vascular smooth muscle contractility
Background: Hypertension is one of high risky factors contributing to thedevelopment of atherosclerosis, a vascular lesion characterized by hardening andthickening of the blood vessel wall. Under certain pathological conditions, such asoxidative stress, vascular smooth muscle (SM) loses its contractility or smoothmuscle cells (SMCs) do not contract properly in response to various vasoactivefactors. Prolonged loss of contractility results in wall stiffness of the blood vessel andmay lead to subsequent hypertension. In many other cases, however, vascular SM hasincreased contractile reactivity than normal subjects, leading to persistentvasoconstriction and hypertension. In the later, one of the most efficient treatments isto relax the blood vessel or to inhibit vascular hyper-contractility. Our preliminarystudies have shown that atorvastatin (ATV), an inhibitor of3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase and a widelyprescribed lipid-lowering drug, has potential inhibitory effects on the expression ofSM contractile proteins and contractility. In addition, our preliminary studies havedemonstrated that treatment with hydrogen peroxide (H_2O_2), an oxidative stressinducer, resulted in an irreversible loss of vascular SM contractility. Therefore, thisthesis focuses on the mechanisms that regulate SM contraction from two directions:(1) ATV regulates myocardin expression and the involvement of the RhoA-ROCKpathway;(2) H_2O_2inhibits vascular SM contractility through a rapamycin-sensitivepathway.
Part-I ATV inhibits vascular contractility through suppression ofmyocardin expression
In addition to lipid-lowing effects, ATV inhibits the RhoA-Rho-associatedkinase (ROCK) pathway in vascular SMCs and critically inhibits SM function.Myocardin is a co-activator of serum response factor (SRF), which up-regulates smooth muscle contractile proteins. The RhoA-ROCK pathway, which directlytriggers SM contraction, also increases myocardin gene expression. Therefore weinvestigated whether ATV inhibits myocardin gene expression in SMCs.
In mice injected with ATV (i.p.20μg/g/d) for5天, myocardin gene expressionwas significantly down-regulated in aortic and carotid arterial tissues with decreasedexpression of myocardin target genes, SM α-actin and SM22. Correspondingly, thecontractility of aortic rings in mice treated with ATV or the ROCK inhibitor Y-27632was reduced in response to treatment with either KCl or phenylephrine. In culturedmouse and human aortic SMCs, KCl treatment stimulated the expression ofmyocardin, SM α-actin and SM22. These stimulatory effects were prevented by ATVtreatment. ATV-induced inhibition of myocardin expression was prevented bypre-treatment with either mevalonate or geranylgeranyl pyrophosphate, but notfarnesyl pyrophosphate. Treatment with Y-27632mimicked ATV-effects on the geneexpression of myocardin, SM α-actin and SM22, further suggesting a role for theRhoA-ROCK pathway in ATV effects. Furthermore, ATV treatment inhibited RhoAmembrane translocation and activation; these effects were prevented by pre-treatmentwith mevalonate. We conclude that ATV inhibits myocardin gene expression in vivoand in vitro, suggesting a novel mechanism for ATV inhibition of vascularcontraction.
Part-II H_2O_2induces loss of vascular SM contractility through aRapamycin-sensitive mechanism
Rapamycin, an inhibitor of the mammalian target of Rapamycin (mTOR)pathway, has been shown to extend the lifespan of mice, and oxidative stress playscritical roles in vascular aging involving loss of compliance of arteries. We examined,therefore, whether Rapamycin has protective effects on the inhibition of vascular SMcontractility by H_2O_2.
Prolonged (3h) exposure to H_2O_2induced complete loss of contraction of mouseaortic rings to either KCl or phenylephrine, which was prevented by pre-treatmentwith Rapamycin. H_2O_2-induced loss of contractility was unaffected by treatment withactinomycin D or cycloheximide, inhibitors of gene transcription and protein synthesis, respectively. Western blot analysis showed that there was no increase inphosphorylation of S6K or4EBP1in response to H_2O_2treatment, suggestinginvolvement of the mTOR complex-2(mTORC2). H_2O_2treatment inhibitedphosphorylation of the20kDa regulatory light chains of myosin (MLC20), whichwas partially blocked by Rapamycin treatment. Interestingly, the calcineurininhibitors cyclosporine A and FK506were found to mimic the Rapamycin effect, andRapamycin inhibited calcineurin activation induced by H_2O_2. We conclude thatRapamycin inhibits H_2O_2-induced loss of vascular contractility, likely through anmTORC2-calcineurin pathway.
Conclusions: Based on above results, we conclude that (1) ATV inhibition ofvascular SM contractility may be beneficial to its treatment in hypertension;(2)H_2O_2-induced loss of vascular SM contractility may result in vascular dysfunctionand subsequent vascular disease.
某些病理条件下，如氧化应激（oxidative stress），会促使血管平滑肌失去收缩能力，其本质是血管平滑肌细胞对血管活性物质失去正常的生理反应。长期的血管收缩功能丧失会致血管僵硬，对血压产生影响。我们的研究初步证实，过氧化氢（hydrogen peroxide，H_2O_2）能不可逆性的抑制血管收缩，导致血管僵硬；而雷帕霉素（Rapamycin，Rapa）可以减缓此过程的发生。
然而在另外一些情况，血管平滑肌对血管活性物质有比正常情况下更强的反应性，导致血管收缩过强，血管压力升高，亦对血压产生影响。我们的初步研究表明，他汀类降脂药物阿托伐他汀（Atorvastatin，ATV）通过抑制血管平滑肌细胞myocardin的表达来降低动脉血管收缩能力，证明ATV具有潜在的通过抑制血管收缩强度来调控血压的能力。
基于我们的初步研究结果，本论文主要包括两个独立的研究：ATV和H_2O_2各自抑制血管收缩的分子机理。
第一部分ATV通过抑制myocardin表达降低血管平滑肌收缩
目的：除了降血脂效应，他汀类（statins）药物的多效性被广泛关注，特别是其对心脑血管的保护作用，但机制尚不明确。在血管平滑肌细胞，他汀类药物可抑制RhoA-ROCK信号通路抑制平滑肌的功能。Myocardin是血清反应因子（SRF）的辅助因子，能上调平滑肌特异性收缩蛋白的表达，是平滑肌细胞分化的关键因子。RhoA-ROCK信号通路的激活可直接触发平滑肌收缩，同时也诱导myocardin基因的表达。因此我们研究他汀类药物的血管保护作用是否与抑制myocardin的表达有关。
方法与结果：C57小鼠腹腔内连续注射ATV（i.p.20mg/kg/天）5天后，分离心脏、胸主动脉及颈总动脉。蛋白质印迹法（Western blotting）检测myocardin及其下游平滑肌特异蛋白SM α-actin和SM22的表达；实时定量聚合酶链反应（Real-time PolymeRase chain reaction, RT-qPCR）检测myocardin及其下游靶基因SM α-actin和SM22mRNA表达。肌张力描计技术（Myography）检测去内皮的胸主动脉血管环对氯化钾（potassium chloride，KCl）、去氧肾上腺素（phenylephrine，PE）等血管活性物的反应。同时，Myography）检测未经ATV处理的C57小鼠胸主动脉血管环ATV（500μM）及ROCK抑制剂Y-27632（10μM）孵育90min前后对KCl和PE的反应。
小鼠及人的主动脉平滑肌细胞系（mSMCs和hSMCs），0%血清培养基饥饿24h后以KCl（60mM）处理细胞24h，RT-qPCR技术检测可知KCl刺激myocardin及其下游靶基因SM α-actin和SM22mRNA表达；这种刺激效应能被ATV（1μM，10μM）抑制。甲羟戊酸（Meva，300μM），香叶基香叶基焦磷酸酯（GGPP，1μM）可逆转ATV的抑制，而法尼基焦磷酸酯（FPP，1μM）不能。ROCK抑制剂Y-27632（10μM）可模拟ATV对myocardin及其下游靶基因SM α-actin和SM22mRNA表达的抑制效应，提示RhoA-ROCK通路与之有关。以Triton X-114萃取法、超速离心、Pull-down及Western blotting技术检测，ATV（100μM）处理的hSMCs的RhoA的法尼基化、胞膜转位及活化均明显降低，而Meva（300μM）可逆转该作用。
第二部分H_2O_2通过Rapa敏感机制诱导血管平滑肌收缩抑制
目的：氧化应激能使血管顺应性降低，在血管老化中扮演了重要角色。Rapa是哺乳动物雷帕霉素靶蛋白（the mammalian target of rapamycin，mTOR）特异性的抑制剂。而Rapa具有延长小鼠寿命、减缓衰老的作用。因此，我们通过Rapa研究H_2O_2对小鼠动脉血管收缩抑制的机理。
方法与结果：用Myography技术检测小鼠胸主动脉及肠系膜动脉（阻力血管）血管环暴露在H_2O_2（200μM）3h前后KCl（50mM）和PE（1μM）诱导收缩的变化。H_2O_2不可逆性的完全抑制血管环的收缩功能；若提前20min加入雷帕霉素（20μM），血管环的收缩能力被部分保留；蛋白合成抑制剂放线菌素D（Act D，1μM）和基因转录抑制剂环孢素（CHX，10μM）不具有保护作用；而钙调神经磷酸酶（calcineurin，CaN）的抑制剂环孢素A（CsA，1μM）和FK506（1μM）能模拟Rapa的保护作用。
蛋白印迹分析法（Western blotting）显示H_2O_2处理动脉环的mTORC1下游底物40s核糖体蛋白S6激酶（S6K）和真核细胞启动因子4E结合蛋白（4EBP1）的磷酸化未增加，提示H_2O_2对mTOR通路的激活未通过mTORC1，而可能与mTORC2有关。H_2O_2抑制的平滑肌肌球蛋白轻链20kD亚基（MLC20）的磷酸化，而该作用能被Rapa部分阻断。
CaN活性测定显示，H_2O_2能增加CaN的活化，该作用可被雷帕霉素所抑制。
结论：基于以上两方面的研究，我们认为：（1）ATV通过抑制myocardin的表达，降低血管平滑肌收缩能力；该机制与RhoA-ROCK通路有关。该研究提示ATV通过对血管收缩能力的抑制，可能成为他汀类药物治疗高血压的依据；（2）H_2O_2对血管收缩功能具有损伤作用，而Rapa对该损伤作用具有保护效应；其机制与mTOR通路的调节有关。该研究提示mTOR通路可能作为氧化损伤导致的血管收缩功能异常的治疗靶点。
The mechanisms underlying inhibitory effects of atorvastatin andhydrogen peroxide on vascular smooth muscle contractility
Background: Hypertension is one of high risky factors contributing to thedevelopment of atherosclerosis, a vascular lesion characterized by hardening andthickening of the blood vessel wall. Under certain pathological conditions, such asoxidative stress, vascular smooth muscle (SM) loses its contractility or smoothmuscle cells (SMCs) do not contract properly in response to various vasoactivefactors. Prolonged loss of contractility results in wall stiffness of the blood vessel andmay lead to subsequent hypertension. In many other cases, however, vascular SM hasincreased contractile reactivity than normal subjects, leading to persistentvasoconstriction and hypertension. In the later, one of the most efficient treatments isto relax the blood vessel or to inhibit vascular hyper-contractility. Our preliminarystudies have shown that atorvastatin (ATV), an inhibitor of3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase and a widelyprescribed lipid-lowering drug, has potential inhibitory effects on the expression ofSM contractile proteins and contractility. In addition, our preliminary studies havedemonstrated that treatment with hydrogen peroxide (H_2O_2), an oxidative stressinducer, resulted in an irreversible loss of vascular SM contractility. Therefore, thisthesis focuses on the mechanisms that regulate SM contraction from two directions:(1) ATV regulates myocardin expression and the involvement of the RhoA-ROCKpathway;(2) H_2O_2inhibits vascular SM contractility through a rapamycin-sensitivepathway.
Part-I ATV inhibits vascular contractility through suppression ofmyocardin expression
In addition to lipid-lowing effects, ATV inhibits the RhoA-Rho-associatedkinase (ROCK) pathway in vascular SMCs and critically inhibits SM function.Myocardin is a co-activator of serum response factor (SRF), which up-regulates smooth muscle contractile proteins. The RhoA-ROCK pathway, which directlytriggers SM contraction, also increases myocardin gene expression. Therefore weinvestigated whether ATV inhibits myocardin gene expression in SMCs.
In mice injected with ATV (i.p.20μg/g/d) for5天, myocardin gene expressionwas significantly down-regulated in aortic and carotid arterial tissues with decreasedexpression of myocardin target genes, SM α-actin and SM22. Correspondingly, thecontractility of aortic rings in mice treated with ATV or the ROCK inhibitor Y-27632was reduced in response to treatment with either KCl or phenylephrine. In culturedmouse and human aortic SMCs, KCl treatment stimulated the expression ofmyocardin, SM α-actin and SM22. These stimulatory effects were prevented by ATVtreatment. ATV-induced inhibition of myocardin expression was prevented bypre-treatment with either mevalonate or geranylgeranyl pyrophosphate, but notfarnesyl pyrophosphate. Treatment with Y-27632mimicked ATV-effects on the geneexpression of myocardin, SM α-actin and SM22, further suggesting a role for theRhoA-ROCK pathway in ATV effects. Furthermore, ATV treatment inhibited RhoAmembrane translocation and activation; these effects were prevented by pre-treatmentwith mevalonate. We conclude that ATV inhibits myocardin gene expression in vivoand in vitro, suggesting a novel mechanism for ATV inhibition of vascularcontraction.
Part-II H_2O_2induces loss of vascular SM contractility through aRapamycin-sensitive mechanism
Rapamycin, an inhibitor of the mammalian target of Rapamycin (mTOR)pathway, has been shown to extend the lifespan of mice, and oxidative stress playscritical roles in vascular aging involving loss of compliance of arteries. We examined,therefore, whether Rapamycin has protective effects on the inhibition of vascular SMcontractility by H_2O_2.
Prolonged (3h) exposure to H_2O_2induced complete loss of contraction of mouseaortic rings to either KCl or phenylephrine, which was prevented by pre-treatmentwith Rapamycin. H_2O_2-induced loss of contractility was unaffected by treatment withactinomycin D or cycloheximide, inhibitors of gene transcription and protein synthesis, respectively. Western blot analysis showed that there was no increase inphosphorylation of S6K or4EBP1in response to H_2O_2treatment, suggestinginvolvement of the mTOR complex-2(mTORC2). H_2O_2treatment inhibitedphosphorylation of the20kDa regulatory light chains of myosin (MLC20), whichwas partially blocked by Rapamycin treatment. Interestingly, the calcineurininhibitors cyclosporine A and FK506were found to mimic the Rapamycin effect, andRapamycin inhibited calcineurin activation induced by H_2O_2. We conclude thatRapamycin inhibits H_2O_2-induced loss of vascular contractility, likely through anmTORC2-calcineurin pathway.
Conclusions: Based on above results, we conclude that (1) ATV inhibition ofvascular SM contractility may be beneficial to its treatment in hypertension;(2)H_2O_2-induced loss of vascular SM contractility may result in vascular dysfunctionand subsequent vascular disease.
引文
[1] Jiang J, Roman RJ. Lovastatin prevents development of hypertension in spontaneouslyhypertensive rats. Hypertension,1997,30:968-974
[2] Wassmann S, Laufs U, Baumer AT, et al. Hmg-coa reductase inhibitors improveendothelial dysfunction in normocholesterolemic hypertension via reduced production ofreactive oxygen species. Hypertension,2001,37:1450-1457
[3] Feldstein CA. Statins in hypertension: Are they a new class of antihypertensive agents?Am J Ther,2010,17:255-262
[4] Qiu H, Zhu Y, Sun Z, et al. Short communication: Vascular smooth muscle cell stiffnessas a mechanism for increased aortic stiffness with aging. Circ Res,2010,107:615-619
[5] Redheuil A, Yu WC, Wu CO, et al. Reduced ascending aortic strain and distensibility:Earliest manifestations of vascular aging in humans. Hypertension,2010,55:319-326
[6] Sawabe M. Vascular aging: From molecular mechanism to clinical significance. GeriatrGerontol Int,2010,10Suppl1:S213-220
[7] McCrann DJ, Yang D, Chen H, et al. Upregulation of nox4in the aging vasculature andits association with smooth muscle cell polyploidy. Cell Cycle,2009,8:902-908
[8] Briones AM, Touyz RM. Oxidative stress and hypertension: Current concepts. CurrHypertens Rep,2010,12:135-142
[9] Ceriello A. Possible role of oxidative stress in the pathogenesis of hypertension. DiabetesCare,2008,31Suppl2:S181-184
[10] Oliveira-Sales EB, Dugaich AP, Carillo BA, et al. Oxidative stress contributes torenovascular hypertension. Am J Hypertens,2008,21:98-104
[11] Marczin N, Ryan US, Catravas JD. Effects of oxidant stress on endothelium-derivedrelaxing factor-induced and nitrovasodilator-induced cgmp accumulation in vascular cellsin culture. Circ Res,1992,70:326-340
[12] Messent M, Griffiths MJ, Quinlan GJ, et al. Ischaemia--reperfusion injury in the rat ismodulated by superoxide generation and leads to an augmentation of the hypoxicpulmonary vascular response. Clin Sci (Lond),1996,90:47-54
[13] Konishi A, Aizawa T, Mohan A, et al. Hydrogen peroxide activates the gas6-axl pathwayin vascular smooth muscle cells. J Biol Chem,2004,279:28766-28770
[14] Li J, Li W, Su J, et al. Hydrogen peroxide induces apoptosis in cerebral vascular smoothmuscle cells: Possible relation to neurodegenerative diseases and strokes. Brain Res Bull,2003,62:101-106
[15] Caldini R, Chevanne M, Mocali A, et al. Premature induction of aging in sublethallyh2o2-treated young mrc5fibroblasts correlates with increased glutathione peroxidaselevels and resistance to DNA breakage. Mech Ageing Dev,1998,105:137-150
[16] Herrero A, Barja G. H2o2production of heart mitochondria and aging rate are slower incanaries and parakeets than in mice: Sites of free radical generation and mechanismsinvolved. Mech Ageing Dev,1998,103:133-146
[17] Jin N, Rhoades RA. Activation of tyrosine kinases in h2o2-induced contraction inpulmonary artery. Am J Physiol,1997,272:H2686-2692
[18] Colavitti R, Finkel T. Reactive oxygen species as mediators of cellular senescence.IUBMB Life,2005,57:277-281
[19] Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of ageing. Nature,2000,408:239-247
[20] Xu Z, Tung VW. Overexpression of neurofilament subunit m accelerates axonal transportof neurofilaments. Brain Res,2000,866:326-332
[21] Brown MS, Goldstein JL. Multivalent feedback regulation of hmg coa reductase, acontrol mechanism coordinating isoprenoid synthesis and cell growth. J Lipid Res,1980,21:505-517
[22]张金盈.急性心肌梗死现代治疗策略.河南：郑州大学出版社,2005
[23] Davignon J, Mabile L. Mechanisms of action of statins and their pleiotropic effects. AnnEndocrinol (Paris),2001,62:101-112
[24] Galus R, Zandecki L, Jozwiak J, et al. Statins and their pleiotropic effects. Pol MerkurLekarski,2008,24:545-548
[25]龚建祖.他汀类药物临床应用进展.临床合理用药,2011, Vol.4:5-7
[26] Zhou Q, Liao JK. Rho kinase: An important mediator of atherosclerosis and vasculardisease. Curr Pharm Des,2009,15:3108-3115
[27] Derk CT, Jimenez SA. Statins and the vasculopathy of systemic sclerosis: Potentialtherapeutic agents? Autoimmun Rev,2006,5:25-32
[28] Erl W, Hristov M, Neureuter M, et al. Hmg-coa reductase inhibitors induce apoptosis inneointima-derived vascular smooth muscle cells. Atherosclerosis,2003,169:251-258
[29] Bellosta S, Bernini F, Ferri N, et al. Direct vascular effects of hmg-coa reductaseinhibitors. Atherosclerosis,1998,137Suppl:S101-109
[30] Corsini A, Pazzucconi F, Arnaboldi L, et al. Direct effects of statins on the vascular wall.J Cardiovasc Pharmacol,1998,31:773-778
[31] Negre-Aminou P, van Vliet AK, van Erck M, et al. Inhibition of proliferation of humansmooth muscle cells by various hmg-coa reductase inhibitors; comparison with otherhuman cell types. Biochim Biophys Acta,1997,1345:259-268
[32] Yamamoto T, Takeda K, Harada S, et al. Hmg-coa reductase inhibitor enhances induciblenitric oxide synthase expression in rat vascular smooth muscle cells; involvement of therho/rho kinase pathway. Atherosclerosis,2003,166:213-222
[33] Ortego M, Gomez-Hernandez A, Vidal C, et al. Hmg-coa reductase inhibitors reduce ikappa b kinase activity induced by oxidative stress in monocytes and vascular smoothmuscle cells. J Cardiovasc Pharmacol,2005,45:468-475
[34] Dichtl W, Dulak J, Frick M, et al. Hmg-coa reductase inhibitors regulate inflammatorytranscription factors in human endothelial and vascular smooth muscle cells. ArteriosclerThromb Vasc Biol,2003,23:58-63
[35] Miyashita Y, Ozaki H, Koide N, et al. Oxysterol-induced apoptosis of vascular smoothmuscle cells is reduced by hmg-coa reductase inhibitor, pravastatin. J AtherosclerThromb,2002,9:65-71
[36] Salonen R, Salonen JT. Carotid atherosclerosis in relation to systolic and diastolic bloodpressure: Kuopio ischaemic heart disease risk factor study. Ann Med,1991,23:23-27
[37] Lloyd-Jones DM, Evans JC, Larson MG, et al. Cross-classification of jnc vi bloodpressure stages and risk groups in the framingham heart study. Arch Intern Med,1999,159:2206-2212
[38] Thomas F, Bean K, Guize L, et al. Combined effects of systolic blood pressure and serumcholesterol on cardiovascular mortality in young (<55years) men and women. Eur HeartJ,2002,23:528-535
[39] Stern N, Grosskopf I, Shapira I, et al. Risk factor clustering in hypertensive patients:Impact of the reports of ncep-ii and second joint task force on coronary prevention onjnc-vi guidelines. J Intern Med,2000,248:203-210
[40] Abbott RD, Rodriguez BL, Petrovitch H, et al. Ankle-brachial blood pressure in elderlymen and the risk of stroke: The honolulu heart program. J Clin Epidemiol,2001,54:973-978
[41] Liao J, Farmer JA. Statins as adjunctive therapy in the management of hypertension. CurrAtheroscler Rep,2010,12:349-354
[42] Goode GK, Miller JP, Heagerty AM. Hyperlipidaemia, hypertension, and coronary heartdisease. Lancet,1995,345:362-364
[43] Sung BH, Izzo JL, Jr., Wilson MF. Effects of cholesterol reduction on bp response tomental stress in patients with high cholesterol. Am J Hypertens,1997,10:592-599
[44] Straznicky NE, Howes LG, Lam W, et al. Effects of pravastatin on cardiovascularreactivity to norepinephrine and angiotensin ii in patients with hypercholesterolemia andsystemic hypertension. Am J Cardiol,1995,75:582-586
[45] Jarai Z, Kapocsi J, Farsang C, et al. Effect of fluvastatin on serum lipid levels in essentialhypertension. Orv Hetil,1996,137:1857-1859
[46] Laufs U, La Fata V, Plutzky J, et al. Upregulation of endothelial nitric oxide synthase byhmg coa reductase inhibitors. Circulation,1998,97:1129-1135
[47] Abetel G, Poget PN, Bonnabry JP. Hypotensive effect of an inhibitor of cholesterolsynthesis (fluvastatin). A pilot study. Schweiz Med Wochenschr,1998,128:272-277
[48] Borghi C, Prandin MG, Costa FV, et al. Use of statins and blood pressure control intreated hypertensive patients with hypercholesterolemia. J Cardiovasc Pharmacol,2000,35:549-555
[49] Glorioso N, Troffa C, Filigheddu F, et al. Effect of the hmg-coa reductase inhibitors onblood pressure in patients with essential hypertension and primary hypercholesterolemia.Hypertension,1999,34:1281-1286
[50] King DE, Mainous AG,3rd, Egan BM, et al. Use of statins and blood pressure. Am JHypertens,2007,20:937-941
[51] Strazzullo P, Kerry SM, Barbato A, et al. Do statins reduce blood pressure?: Ameta-analysis of randomized, controlled trials. Hypertension,2007,49:792-798
[52] Kostapanos MS, Milionis HJ, Elisaf MS. Current role of statins in the treatment ofessential hypertension. Expert Opin Pharmacother,2010,11:2635-2650
[53] Reckless JP. Cholesterol metabolism in arterial smooth muscle and endothelium.Biochem Soc Trans,1978,6:883-887
[54] Arai Y, Sasaki M, Sakuragawa N. Hypoxic effects on cholesterol metabolism of culturedrat aortic and brain microvascular endothelial cells, and aortic vascular smooth musclecells. Tohoku J Exp Med,1996,180:17-25
[55] Weivoda MM, Hohl RJ. Effects of farnesyl pyrophosphate accumulation on calvarialosteoblast differentiation. Endocrinology,2011,152:3113-3122
[56] Yamada H. Ultrastructure of smooth muscle fibers. Nihon Heikatsukin Gakkai Zasshi,1974,10:113-116
[57] Somlyo AP. Excitation-contraction coupling and the ultrastructure of smooth muscle.Circ Res,1985,57:497-507
[58] Somlyo AP. Cell physiology: Cellular site of calcium regulation. Nature,1984,309:516-517
[59] Somlyo AP, Somlyo AV, Kitazawa T, et al. Ultrastructure, function and composition ofsmooth muscle. Ann Biomed Eng,1983,11:579-588
[60] Calcium channel-blocking drugs: A novel intervention for the treatment of cardiacdisease. Proceedings of the symposium on calcium blocking agents. July25-26,1981,tokyo, japan. Circ Res,1983,52:I1-181
[61] Bond M, Kitazawa T, Somlyo AP, et al. Release and recycling of calcium by thesarcoplasmic reticulum in guinea-pig portal vein smooth muscle. J Physiol,1984,355:677-695
[62] Bond M, Shuman H, Somlyo AP, et al. Total cytoplasmic calcium in relaxed andmaximally contracted rabbit portal vein smooth muscle. J Physiol,1984,357:185-201
[63] Carbone E, Lux HD. A low voltage-activated, fully inactivating ca channel in vertebratesensory neurones. Nature,1984,310:501-502
[64] Bezanilla F, Stefani E. Voltage-dependent gating of ionic channels. Annu Rev BiophysBiomol Struct,1994,23:819-846
[65] Casteels R. Electro-and pharmacomechanical coupling in vascular smooth muscle. Chest,1980,78:150-156
[66] Nowycky MC, Fox AP, Tsien RW. Three types of neuronal calcium channel withdifferent calcium agonist sensitivity. Nature,1985,316:440-443
[67] Akhtar RA, Abdel-Latif AA. Carbachol causes rapid phosphodiesteratic cleavage ofphosphatidylinositol4,5-bisphosphate and accumulation of inositol phosphates in rabbitiris smooth muscle; prazosin inhibits noradrenaline-and ionophore a23187-stimulatedaccumulation of inositol phosphates. Biochem J,1984,224:291-300
[68] Burgess GM, Irvine RF, Berridge MJ, et al. Actions of inositol phosphates on ca2+poolsin guinea-pig hepatocytes. Biochem J,1984,224:741-746
[69] Blaustein MP. Sodium ions, calcium ions, blood pressure regulation, and hypertension: Areassessment and a hypothesis. Am J Physiol,1977,232:C165-173
[70]廖家培.钙离子：进入细胞浆的途径与血管平滑肌收缩机制.生理科学进展,1989,Vol.20:49-52
[71] Streb H, Schulz I. Regulation of cytosolic free ca2+concentration in acinar cells of ratpancreas. Am J Physiol,1983,245:G347-357
[72] Streb H, Irvine RF, Berridge MJ, et al. Release of ca2+from a nonmitochondrialintracellular store in pancreatic acinar cells by inositol-1,4,5-trisphosphate. Nature,1983,306:67-69
[73] Headings VE, Rondell PA. Arterial muscle contraction and potassium movement in vitro.Am J Physiol,1962,202:17-20
[74] Klee CB, Crouch TH, Richman PG. Calmodulin. Annu Rev Biochem,1980,49:489-515
[75] Sobieszek A, Small JV. Regulation of the actin-myosin interaction in vertebrate smoothmuscle: Activation via a myosin light-chain kinase and the effect of tropomyosin. J MolBiol,1977,112:559-576
[76] Adelstein RS, Klee CB. Purification of smooth muscle myosin light-chain kinase.Methods Enzymol,1982,85Pt B:298-308
[77] Adelstein RS. Calmodulin and the regulation of the actin-myosin interaction in smoothmuscle and nonmuscle cells. Cell,1982,30:349-350
[78] Adelstein RS, Pato MD, Sellers JR, et al. Regulation of contractile proteins by reversiblephosphorylation of myosin and myosin kinase. Soc Gen Physiol Ser,1982,37:273-281
[79] Adelstein RS, Sellers JR, Conti MA, et al. Regulation of smooth muscle contractileproteins by calmodulin and cyclic amp. Fed Proc,1982,41:2873-2878
[80] Walsh FS, Doherty P. Factors regulating the expression and function ofcalcium-independent cell adhesion molecules. Curr Opin Cell Biol,1993,5:791-796
[81] Ikebe M, Hartshorne DJ. Conformation-dependent proteolysis of smooth-muscle myosin.J Biol Chem,1984,259:11639-11642
[82] Somlyo AP, Somlyo AV. Signal transduction and regulation in smooth muscle. Nature,1994,372:231-236
[83]成建国,杨光明.动脉血压的形成与影响血压正常值的常见因素.西藏医药杂志,2004, Vol.25:31-34
[84] Hauschka SD. Myocardin. A novel potentiator of srf-mediated transcription in cardiacmuscle. Mol Cell,2001,8:1-2
[85] Wang D, Chang PS, Wang Z, et al. Activation of cardiac gene expression by myocardin,a transcriptional cofactor for serum response factor. Cell,2001,105:851-862
[86] Wang DZ, Li S, Hockemeyer D, et al. Potentiation of serum response factor activity by afamily of myocardin-related transcription factors. Proc Natl Acad Sci U S A,2002,99:14855-14860
[87] Doi H, Iso T, Yamazaki M, et al. Herp1inhibits myocardin-induced vascular smoothmuscle cell differentiation by interfering with srf binding to carg box. ArteriosclerThromb Vasc Biol,2005,25:2328-2334
[88] Li S, Wang DZ, Wang Z, et al. The serum response factor coactivator myocardin isrequired for vascular smooth muscle development. Proc Natl Acad Sci U S A,2003,100:9366-9370
[89] Owens GK, Kumar MS, Wamhoff BR. Molecular regulation of vascular smooth musclecell differentiation in development and disease. Physiol Rev,2004,84:767-801
[90] Yoshida T, Sinha S, Dandre F, et al. Myocardin is a key regulator of carg-dependenttranscription of multiple smooth muscle marker genes. Circ Res,2003,92:856-864
[91] Creemers EE, Sutherland LB, McAnally J, et al. Myocardin is a direct transcriptionaltarget of mef2, tead and foxo proteins during cardiovascular development. Development(Cambridge, England),2006,133:4245-4256
[92] Li S, Chang S, Qi X, et al. Requirement of a myocardin-related transcription factor fordevelopment of mammary myoepithelial cells. Molecular and cellular biology,2006,26:5797-5808
[93] Shore P, Sharrocks AD. The mads-box family of transcription factors. Eur J Biochem,1995,229:1-13
[94] Rensen SS, Niessen PM, Long X, et al. Contribution of serum response factor andmyocardin to transcriptional regulation of smoothelins. Cardiovasc Res,2006,70:136-145
[95] Yoshida T, Kawai-Kowase K, Owens GK. Forced expression of myocardin is notsufficient for induction of smooth muscle differentiation in multipotential embryoniccells. Arterioscler Thromb Vasc Biol,2004,24:1596-1601
[96] Li J, Zhu X, Chen M, et al. Myocardin-related transcription factor b is required in cardiacneural crest for smooth muscle differentiation and cardiovascular development. Proc NatlAcad Sci U S A,2005,102:8916-8921
[97] Goss AM, Tian Y, Cheng L, et al. Wnt2signaling is necessary and sufficient to activatethe airway smooth muscle program in the lung by regulating myocardin/mrtf-b and fgf10expression. Dev Biol,2011,356:541-552
[98] Miano JM. Cardiac-specific gene expression: A handful of factors. J Mol Cell Cardiol,2002,34:1287-1291
[99] Shimokawa H, Takeshita A. Rho-kinase is an important therapeutic target incardiovascular medicine. Arterioscler Thromb Vasc Biol,2005,25:1767-1775
[100] Shirai H, Autieri M, Eguchi S. Small gtp-binding proteins and mitogen-activated proteinkinases as promising therapeutic targets of vascular remodeling. Curr Opin NephrolHypertens,2007,16:111-115
[101] Parsons JT. Integrin-mediated signalling: Regulation by protein tyrosine kinases andsmall gtp-binding proteins. Curr Opin Cell Biol,1996,8:146-152
[102] Wang Y, Zheng XR, Riddick N, et al. Rock isoform regulation of myosin phosphataseand contractility in vascular smooth muscle cells. Circ Res,2009,104:531-540
[103] Zhang W, Du L, Gunst SJ. The effects of the small gtpase rhoa on the muscariniccontraction of airway smooth muscle result from its role in regulating actinpolymerization. Am J Physiol Cell Physiol,2010,299:C298-306
[104] Ogita H, Kunimoto S, Kamioka Y, et al. Epha4-mediated rho activation via vsm-rhogefexpressed specifically in vascular smooth muscle cells. Circ Res,2003,93:23-31
[105] Guilluy C, Eddahibi S, Agard C, et al. Rhoa and rho kinase activation in humanpulmonary hypertension: Role of5-ht signaling. Am J Respir Crit Care Med,2009,179:1151-1158
[106] Loirand G, Guerin P, Pacaud P. Rho kinases in cardiovascular physiology andpathophysiology. Circ Res,2006,98:322-334
[107] Janssen LJ, Tazzeo T, Zuo J, et al. Kcl evokes contraction of airway smooth muscle viaactivation of rhoa and rho-kinase. Am J Physiol Lung Cell Mol Physiol,2004,287:L852-858
[108] Bergdahl A, Persson E, Hellstrand P, et al. Lovastatin induces relaxation and inhibitsl-type ca(2+) current in the rat basilar artery. Pharmacol Toxicol,2003,93:128-134
[109] Wamhoff BR, Bowles DK, McDonald OG, et al. L-type voltage-gated ca2+channelsmodulate expression of smooth muscle differentiation marker genes via a rhokinase/myocardin/srf-dependent mechanism. Circ Res,2004,95:406-414
[110] Lagna G, Ku MM, Nguyen PH, et al. Control of phenotypic plasticity of smooth musclecells by bone morphogenetic protein signaling through the myocardin-relatedtranscription factors. J Biol Chem,2007,282:37244-37255
[111] Fibbi B, Morelli A, Marini M, et al. Atorvastatin but not elocalcitol increases sildenafilresponsiveness in spontaneously hypertensive rats by regulating the rhoa/rock pathway. JAndrol,2008,29:70-84
[112] Liao JK. Effects of statins on3-hydroxy-3-methylglutaryl coenzyme a reductaseinhibition beyond low-density lipoprotein cholesterol. Am J Cardiol,2005,96:24F-33F
[113] Van Aelst L, D'Souza-Schorey C. Rho gtpases and signaling networks. Genes Dev,1997,11:2295-2322
[114] Dharmawardhane S, Bokoch GM. Rho gtpases and leukocyte cytoskeletal regulation.Curr Opin Hematol,1997,4:12-18
[115] Fedoruk LM, Wang H, Conaway MR, et al. Statin therapy improves outcomes aftervalvular heart surgery. Ann Thorac Surg,2008,85:1521-1525; discussion1525-1526
[116] Wang CY, Liu PY, Liao JK. Pleiotropic effects of statin therapy: Molecular mechanismsand clinical results. Trends Mol Med,2008,14:37-44
[117] Hall A. Rho gtpases and the actin cytoskeleton. Science,1998,279:509-514
[118] Mackay DJ, Hall A. Rho gtpases. J Biol Chem,1998,273:20685-20688
[119] Li M, Liu Y, Dutt P, et al. Inhibition of serotonin-induced mitogenesis, migration, anderk mapk nuclear translocation in vascular smooth muscle cells by atorvastatin. Am JPhysiol Lung Cell Mol Physiol,2007,293:L463-471
[120] Chapman RH, Petrilla AA, Berman L, et al. Are high-risk hypertensive patients beingprescribed concomitant statin therapy?: A retrospective cohort study. Am J CardiovascDrugs,2009,9:299-308
[121] Uehata M, Ishizaki T, Satoh H, et al. Calcium sensitization of smooth muscle mediatedby a rho-associated protein kinase in hypertension. Nature,1997,389:990-994
[122] Kureishi Y, Kobayashi S, Amano M, et al. Rho-associated kinase directly inducessmooth muscle contraction through myosin light chain phosphorylation. J Biol Chem,1997,272:12257-12260
[123] Matsuo Y, Kuwabara M, Tanaka-Totoribe N, et al. The defective protein level of myosinlight chain phosphatase (mlcp) in the isolated saphenous vein, as a vascular conduit incoronary artery bypass grafting (cabg), harvested from patients with diabetes mellitus(dm). Biochem Biophys Res Commun,2011,412:323-327
[124] Rattan S.3-hydroxymethyl coenzyme a reductase inhibition attenuates spontaneoussmooth muscle tone via rhoa/rock pathway regulated by rhoa prenylation. Am J PhysiolGastrointest Liver Physiol,2010,298:G962-969
[125] Corsini A, Ferri N, Cortellaro M. Are pleiotropic effects of statins real? Vasc Health RiskManag,2007,3:611-613
[126] Laufs U, Liao JK. Isoprenoid metabolism and the pleiotropic effects of statins. CurrAtheroscler Rep,2003,5:372-378
[127] Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol,2005,45:89-118
[128] Zhou Q, Liao JK. Pleiotropic effects of statins.-basic research and clinical perspectives.Circ J,2010,74:818-826
[129] Ye Y, Hu SJ, Li L. Inhibition of farnesylpyrophosphate synthase prevents angiotensinii-induced hypertrophic responses in rat neonatal cardiomyocytes: Involvement of therhoa/rho kinase pathway. FEBS Lett,2009,583:2997-3003
[130] Katayama M, Kawata M, Yoshida Y, et al. The posttranslationally modified c-terminalstructure of bovine aortic smooth muscle rhoa p21. J Biol Chem,1991,266:12639-12645
[131] Adamson P, Marshall CJ, Hall A, et al. Post-translational modifications of p21rhoproteins. J Biol Chem,1992,267:20033-20038
[132] Zhang FL, Casey PJ. Protein prenylation: Molecular mechanisms and functionalconsequences. Annu Rev Biochem,1996,65:241-269
[133] Turner SJ, Zhuang S, Zhang T, et al. Effects of lovastatin on rho isoform expression,activity, and association with guanine nucleotide dissociation inhibitors. BiochemPharmacol,2008,75:405-413
[134] Ruperez M, Rodrigues-Diez R, Blanco-Colio LM, et al. Hmg-coa reductase inhibitorsdecrease angiotensin ii-induced vascular fibrosis: Role of rhoa/rock and mapk pathways.Hypertension,2007,50:377-383
[135] Seko T, Ito M, Kureishi Y, et al. Activation of rhoa and inhibition of myosin phosphataseas important components in hypertension in vascular smooth muscle. Circ Res,2003,92:411-418
[136] Somlyo AP, Somlyo AV. Ca2+sensitivity of smooth muscle and nonmuscle myosin ii:Modulated by g proteins, kinases, and myosin phosphatase. Physiol Rev,2003,83:1325-1358
[137] Mukai Y, Shimokawa H, Matoba T, et al. Involvement of rho-kinase in hypertensivevascular disease: A novel therapeutic target in hypertension. FASEB J,2001,15:1062-1064
[138] Yang L, Gao YJ, Lee RM. The effects of quinapril and atorvastatin on artery structureand function in adult spontaneously hypertensive rats. Eur J Pharmacol,2005,518:145-151
[139] Noma K, Oyama N, Liao JK. Physiological role of rocks in the cardiovascular system.Am J Physiol Cell Physiol,2006,290:C661-668
[140] Lee S, Pagoria D, Raigrodski A, et al. Effects of combinations of ros scavengers onoxidative DNA damage caused by visible-light-activatedcamphorquinone/n,n-dimethyl-p-toluidine. J Biomed Mater Res B Appl Biomater,2007,83:391-399
[141] Castilho RF, Carvalho-Alves PC, Vercesi AE, et al. Oxidative damage to sarcoplasmicreticulum ca(2+)-pump induced by fe2+/h2o2/ascorbate is not mediated by lipidperoxidation or thiol oxidation and leads to protein fragmentation. Mol Cell Biochem,1996,159:105-114
[142] Herrero A, Portero-Otin M, Bellmunt MJ, et al. Effect of the degree of fatty acidunsaturation of rat heart mitochondria on their rates of h2o2production and lipid andprotein oxidative damage. Mech Ageing Dev,2001,122:427-443
[143] Sotnikova R. Investigation of the mechanisms underlying h2o2-evoked contraction in theisolated rat aorta. Gen Pharmacol,1998,31:115-119
[144] Iesaki T, Okada T, Yamaguchi H, et al. Inhibition of vasoactive amine inducedcontractions of vascular smooth muscle by hydrogen peroxide in rabbit aorta. CardiovascRes,1994,28:963-968
[145] Burke TM, Wolin MS. Hydrogen peroxide elicits pulmonary arterial relaxation andguanylate cyclase activation. Am J Physiol,1987,252:H721-732
[146] Iesaki T, Okada T, Shimada I, et al. Decrease in ca2+sensitivity as a mechanism ofhydrogen peroxide-induced relaxation of rabbit aorta. Cardiovasc Res,1996,31:820-825
[147] Qin S, Chock PB. Implication of phosphatidylinositol3-kinase membrane recruitment inhydrogen peroxide-induced activation of pi3k and akt. Biochemistry,2003,42:2995-3003
[148] Sadidi M, Lentz SI, Feldman EL. Hydrogen peroxide-induced akt phosphorylationregulates bax activation. Biochimie,2009,91:577-585
[149] Faghiri Z, Bazan NG. Pi3k/akt and mtor/p70s6k pathways mediate neuroprotectind1-induced retinal pigment epithelial cell survival during oxidative stress-inducedapoptosis. Exp Eye Res,2010,90:718-725
[150] Hegner B, Lange M, Kusch A, et al. Mtor regulates vascular smooth muscle celldifferentiation from human bone marrow-derived mesenchymal progenitors. ArteriosclerThromb Vasc Biol,2009,29:232-238
[151] Martin KA, Rzucidlo EM, Merenick BL, et al. The mtor/p70s6k1pathway regulatesvascular smooth muscle cell differentiation. Am J Physiol Cell Physiol,2004,286:C507-517
[152] Harrison DE, Strong R, Sharp ZD, et al. Rapamycin fed late in life extends lifespan ingenetically heterogeneous mice. Nature,2009,460:392-395
[153] Sarbassov DD, Ali SM, Sengupta S, et al. Prolonged rapamycin treatment inhibits mtorc2assembly and akt/pkb. Mol Cell,2006,22:159-168
[154] Toschi A, Lee E, Xu L, et al. Regulation of mtorc1and mtorc2complex assembly byphosphatidic acid: Competition with rapamycin. Mol Cell Biol,2009,29:1411-1420
[155] Gibbons JJ, Abraham RT, Yu K. Mammalian target of rapamycin: Discovery ofrapamycin reveals a signaling pathway important for normal and cancer cell growth.Semin Oncol,2009,36Suppl3:S3-S17
[156] Sparks CA, Guertin DA. Targeting mtor: Prospects for mtor complex2inhibitors incancer therapy. Oncogene,2010,29:3733-3744
[157] Huang J, Manning BD. A complex interplay between akt, tsc2and the two mtorcomplexes. Biochem Soc Trans,2009,37:217-222
[158] Wang X, Beugnet A, Murakami M, et al. Distinct signaling events downstream of mtorcooperate to mediate the effects of amino acids and insulin on initiation factor4e-bindingproteins. Mol Cell Biol,2005,25:2558-2572
[159] Cheng SW, Fryer LG, Carling D, et al. Thr2446is a novel mammalian target ofrapamycin (mtor) phosphorylation site regulated by nutrient status. J Biol Chem,2004,279:15719-15722
[160] Asnaghi L, Bruno P, Priulla M, et al. Mtor: A protein kinase switching between life anddeath. Pharmacol Res,2004,50:545-549
[161] O'Shea C, Klupsch K, Choi S, et al. Adenoviral proteins mimic nutrient/growth signals toactivate the mtor pathway for viral replication. EMBO J,2005,24:1211-1221
[162] Jastrzebski K, Hannan KM, Tchoubrieva EB, et al. Coordinate regulation of ribosomebiogenesis and function by the ribosomal protein s6kinase, a key mediator of mtorfunction. Growth Factors,2007,25:209-226
[163] Lucchesi PA. Rapamycin plays a new role as differentiator of vascular smooth musclephenotype. Focus on "the mtor/p70s6k1pathway regulates vascular smooth muscledifferentiation". Am J Physiol Cell Physiol,2004,286:C480-481
[164] Kanda T, Hayashi K, Wakino S, et al. Role of rho-kinase and p27in angiotensinii-induced vascular injury. Hypertension,2005,45:724-729
[165] Yao JS, Chen Y, Zhai W, et al. Minocycline exerts multiple inhibitory effects on vascularendothelial growth factor-induced smooth muscle cell migration: The role of erk1/2, pi3k,and matrix metalloproteinases. Circ Res,2004,95:364-371
[166] Panwalkar A, Verstovsek S, Giles FJ. Mammalian target of rapamycin inhibition astherapy for hematologic malignancies. Cancer,2004,100:657-666
[167] Sarbassov DD, Guertin DA, Ali SM, et al. Phosphorylation and regulation of akt/pkb bythe rictor-mtor complex. Science,2005,307:1098-1101
[168] Fraga D, Sehring IM, Kissmehl R, et al. Protein phosphatase2b (pp2b, calcineurin) inparamecium: Partial characterization reveals that two members of the unusually largecatalytic subunit family have distinct roles in calcium dependent processes. Eukaryot Cell,2010,
[169] Roberts-Wilson TK, Reddy RN, Bailey JL, et al. Calcineurin signaling and pgc-1alphaexpression are suppressed during muscle atrophy due to diabetes. Biochim Biophys Acta,2010,
[170] Mackiewicz U, Maczewski M, Klemenska E, et al. Brief postinfarction calcineurinblockade affects left ventricular remodeling and ca2+handling in the rat. J Mol CellCardiol,2010,48:1307-1315
[171] Kubokawa M, Kojo T, Komagiri Y, et al. Role of calcineurin-mediateddephosphorylation in modulation of an inwardly rectifying k+channel in humanproximal tubule cells. J Membr Biol,2009,231:79-92
[172] Mallinson J, Meissner J, Chang KC. Chapter2. Calcineurin signaling and the slowoxidative skeletal muscle fiber type. Int Rev Cell Mol Biol,2009,277:67-101
[173] Dallas A, Khalil RA. Ca2+antagonist-insensitive coronary smooth muscle contractioninvolves activation of epsilon-protein kinase c-dependent pathway. Am J Physiol CellPhysiol,2003,285:C1454-1463
[174] Ghosh R, Emmons SW. Calcineurin and protein kinase g regulate c. Elegans behavioralquiescence during locomotion in liquid. BMC Genet,2010,11:7
[175] Yamashiro T, Kuge H, Zhang J, et al. Calcineurin mediates the angiotensin ii-inducedaldosterone synthesis in the adrenal glands by upregulation of transcription of thecyp11b2gene. J Biochem,2010,
[176] Mano A, Tatsumi T, Shiraishi J, et al. Aldosterone directly induces myocyte apoptosisthrough calcineurin-dependent pathways. Circulation,2004,110:317-323
[177] Tumlin JA, Lea JP, Swanson CE, et al. Aldosterone and dexamethasone stimulatecalcineurin activity through a transcription-independent mechanism involving steroidreceptor-associated heat shock proteins. J Clin Invest,1997,99:1217-1223
[178] Martin-Garrido A, Gonzalez-Ramos M, Griera M, et al. H2o2regulation of vascularfunction through sgc mrna stabilization by hur. Arterioscler Thromb Vasc Biol,2011,31:567-573
[179] Xiao Q, Luo Z, Pepe AE, et al. Embryonic stem cell differentiation into smooth musclecells is mediated by nox4-produced h2o2. Am J Physiol Cell Physiol,2009,296:C711-723
[180] Cascino T, Csanyi G, Al Ghouleh I, et al. Adventitia-derived hydrogen peroxide impairsrelaxation of the rat carotid artery via smooth muscle cell p38mitogen-activated proteinkinase. Antioxid Redox Signal,2011,15:1507-1515
[181] Uetz P, Giot L, Cagney G, et al. A comprehensive analysis of protein-protein interactionsin saccharomyces cerevisiae. Nature,2000,403:623-627
[182] Mulet JM, Martin DE, Loewith R, et al. Mutual antagonism of target of rapamycin andcalcineurin signaling. J Biol Chem,2006,281:33000-33007
[183] Byon CH, Javed A, Dai Q, et al. Oxidative stress induces vascular calcification throughmodulation of the osteogenic transcription factor runx2by akt signaling. J Biol Chem,2008,283:15319-15327
[184] Radisavljevic ZM, Gonzalez-Flecha B. Tor kinase and ran are downstream from pi3k/aktin h2o2-induced mitosis. J Cell Biochem,2004,91:1293-1300
[185] Desai BN, Myers BR, Schreiber SL. Fkbp12-rapamycin-associated protein associateswith mitochondria and senses osmotic stress via mitochondrial dysfunction. Proc NatlAcad Sci U S A,2002,99:4319-4324
[186] Ikenoue T, Inoki K, Yang Q, et al. Essential function of torc2in pkc and akt turn motifphosphorylation, maturation and signalling. EMBO J,2008,27:1919-1931
[187] Tocci MJ, Sigal NH. Recent advances in the mechanism of action of cyclosporine andfk506. Curr Opin Nephrol Hypertens,1992,1:236-242
[188] Leblanc N, Ledoux J, Saleh S, et al. Regulation of calcium-activated chloride channels insmooth muscle cells: A complex picture is emerging. Can J Physiol Pharmacol,2005,83:541-556
[189] Ledoux J, Greenwood I, Villeneuve LR, et al. Modulation of ca2+-dependent cl-channels by calcineurin in rabbit coronary arterial myocytes. J Physiol,2003,552:701-714
[190] Cameron AM, Nucifora FC, Jr., Fung ET, et al. Fkbp12binds the inositol1,4,5-trisphosphate receptor at leucine-proline (1400-1401) and anchors calcineurin tothis fk506-like domain. J Biol Chem,1997,272:27582-27588
[191] Cameron AM, Steiner JP, Sabatini DM, et al. Immunophilin fk506binding proteinassociated with inositol1,4,5-trisphosphate receptor modulates calcium flux. Proc NatlAcad Sci U S A,1995,92:1784-1788
[192] Dargan SL, Lea EJ, Dawson AP. Modulation of type-1ins(1,4,5)p3receptor channels bythe fk506-binding protein, fkbp12. Biochem J,2002,361:401-407
[193] Jahnke T, Schafer FK, Bolte H, et al. Short-term rapamycin for inhibition of neointimaformation after balloon-mediated aortic injury in rats: Is there a window of opportunityfor systemic prophylaxis of restenosis? J Endovasc Ther,2005,12:332-342
[194] Lee KJ, Hinek A, Chaturvedi RR, et al. Rapamycin-eluting stents in the arterial duct:Experimental observations in the pig model. Circulation,2009,119:2078-2085
[195] Hilker M, Buerke M, Guckenbiehl M, et al. Rapamycin reduces neointima formationduring vascular injury. Vasa,2003,32:10-13
[196] Kwon YS, Hong HS, Kim JC, et al. Inhibitory effect of rapamycin on cornealneovascularization in vitro and in vivo. Invest Ophthalmol Vis Sci,2005,46:454-460
[197] Pan M, de Lezo JS, Medina A, et al. Rapamycin-eluting stents for the treatment ofbifurcated coronary lesions: A randomized comparison of a simple versus complexstrategy. Am Heart J,2004,148:857-864
[198] Neto Mde M, Di Marco GS, Casarini DE, et al. Orally administered rapamycin does notmodify rat aortic vascular tone. J Cardiovasc Pharmacol,2007,49:96-99
[199] Antoniades C, Bakogiannis C, Tousoulis D, et al. Preoperative atorvastatin treatment incabg patients rapidly improves vein graft redox state by inhibition of rac1andnadph-oxidase activity. Circulation,2010,122:S66-73
[200] Carnevale R, Pignatelli P, Di Santo S, et al. Atorvastatin inhibits oxidative stress viaadiponectin-mediated nadph oxidase down-regulation in hypercholesterolemic patients.Atherosclerosis,2010,213:225-234
[201] Chiu CZ, Wang BW, Shyu KG. Use of atorvastatin to inhibit hypoxia-induced myocardinexpression. Eur J Clin Invest,2012,42:564-571
[202] Finlay GA, Malhowski AJ, Liu Y, et al. Selective inhibition of growth of tuberoussclerosis complex2null cells by atorvastatin is associated with impaired rheb and rhogtpase function and reduced mtor/s6kinase activity. Cancer Res,2007,67:9878-9886
[2] Wassmann S, Laufs U, Baumer AT, et al. Hmg-coa reductase inhibitors improveendothelial dysfunction in normocholesterolemic hypertension via reduced production ofreactive oxygen species. Hypertension,2001,37:1450-1457
[3] Feldstein CA. Statins in hypertension: Are they a new class of antihypertensive agents?Am J Ther,2010,17:255-262
[4] Qiu H, Zhu Y, Sun Z, et al. Short communication: Vascular smooth muscle cell stiffnessas a mechanism for increased aortic stiffness with aging. Circ Res,2010,107:615-619
[5] Redheuil A, Yu WC, Wu CO, et al. Reduced ascending aortic strain and distensibility:Earliest manifestations of vascular aging in humans. Hypertension,2010,55:319-326
[6] Sawabe M. Vascular aging: From molecular mechanism to clinical significance. GeriatrGerontol Int,2010,10Suppl1:S213-220
[7] McCrann DJ, Yang D, Chen H, et al. Upregulation of nox4in the aging vasculature andits association with smooth muscle cell polyploidy. Cell Cycle,2009,8:902-908
[8] Briones AM, Touyz RM. Oxidative stress and hypertension: Current concepts. CurrHypertens Rep,2010,12:135-142
[9] Ceriello A. Possible role of oxidative stress in the pathogenesis of hypertension. DiabetesCare,2008,31Suppl2:S181-184
[10] Oliveira-Sales EB, Dugaich AP, Carillo BA, et al. Oxidative stress contributes torenovascular hypertension. Am J Hypertens,2008,21:98-104
[11] Marczin N, Ryan US, Catravas JD. Effects of oxidant stress on endothelium-derivedrelaxing factor-induced and nitrovasodilator-induced cgmp accumulation in vascular cellsin culture. Circ Res,1992,70:326-340
[12] Messent M, Griffiths MJ, Quinlan GJ, et al. Ischaemia--reperfusion injury in the rat ismodulated by superoxide generation and leads to an augmentation of the hypoxicpulmonary vascular response. Clin Sci (Lond),1996,90:47-54
[13] Konishi A, Aizawa T, Mohan A, et al. Hydrogen peroxide activates the gas6-axl pathwayin vascular smooth muscle cells. J Biol Chem,2004,279:28766-28770
[14] Li J, Li W, Su J, et al. Hydrogen peroxide induces apoptosis in cerebral vascular smoothmuscle cells: Possible relation to neurodegenerative diseases and strokes. Brain Res Bull,2003,62:101-106
[15] Caldini R, Chevanne M, Mocali A, et al. Premature induction of aging in sublethallyh2o2-treated young mrc5fibroblasts correlates with increased glutathione peroxidaselevels and resistance to DNA breakage. Mech Ageing Dev,1998,105:137-150
[16] Herrero A, Barja G. H2o2production of heart mitochondria and aging rate are slower incanaries and parakeets than in mice: Sites of free radical generation and mechanismsinvolved. Mech Ageing Dev,1998,103:133-146
[17] Jin N, Rhoades RA. Activation of tyrosine kinases in h2o2-induced contraction inpulmonary artery. Am J Physiol,1997,272:H2686-2692
[18] Colavitti R, Finkel T. Reactive oxygen species as mediators of cellular senescence.IUBMB Life,2005,57:277-281
[19] Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of ageing. Nature,2000,408:239-247
[20] Xu Z, Tung VW. Overexpression of neurofilament subunit m accelerates axonal transportof neurofilaments. Brain Res,2000,866:326-332
[21] Brown MS, Goldstein JL. Multivalent feedback regulation of hmg coa reductase, acontrol mechanism coordinating isoprenoid synthesis and cell growth. J Lipid Res,1980,21:505-517
[22]张金盈.急性心肌梗死现代治疗策略.河南：郑州大学出版社,2005
[23] Davignon J, Mabile L. Mechanisms of action of statins and their pleiotropic effects. AnnEndocrinol (Paris),2001,62:101-112
[24] Galus R, Zandecki L, Jozwiak J, et al. Statins and their pleiotropic effects. Pol MerkurLekarski,2008,24:545-548
[25]龚建祖.他汀类药物临床应用进展.临床合理用药,2011, Vol.4:5-7
[26] Zhou Q, Liao JK. Rho kinase: An important mediator of atherosclerosis and vasculardisease. Curr Pharm Des,2009,15:3108-3115
[27] Derk CT, Jimenez SA. Statins and the vasculopathy of systemic sclerosis: Potentialtherapeutic agents? Autoimmun Rev,2006,5:25-32
[28] Erl W, Hristov M, Neureuter M, et al. Hmg-coa reductase inhibitors induce apoptosis inneointima-derived vascular smooth muscle cells. Atherosclerosis,2003,169:251-258
[29] Bellosta S, Bernini F, Ferri N, et al. Direct vascular effects of hmg-coa reductaseinhibitors. Atherosclerosis,1998,137Suppl:S101-109
[30] Corsini A, Pazzucconi F, Arnaboldi L, et al. Direct effects of statins on the vascular wall.J Cardiovasc Pharmacol,1998,31:773-778
[31] Negre-Aminou P, van Vliet AK, van Erck M, et al. Inhibition of proliferation of humansmooth muscle cells by various hmg-coa reductase inhibitors; comparison with otherhuman cell types. Biochim Biophys Acta,1997,1345:259-268
[32] Yamamoto T, Takeda K, Harada S, et al. Hmg-coa reductase inhibitor enhances induciblenitric oxide synthase expression in rat vascular smooth muscle cells; involvement of therho/rho kinase pathway. Atherosclerosis,2003,166:213-222
[33] Ortego M, Gomez-Hernandez A, Vidal C, et al. Hmg-coa reductase inhibitors reduce ikappa b kinase activity induced by oxidative stress in monocytes and vascular smoothmuscle cells. J Cardiovasc Pharmacol,2005,45:468-475
[34] Dichtl W, Dulak J, Frick M, et al. Hmg-coa reductase inhibitors regulate inflammatorytranscription factors in human endothelial and vascular smooth muscle cells. ArteriosclerThromb Vasc Biol,2003,23:58-63
[35] Miyashita Y, Ozaki H, Koide N, et al. Oxysterol-induced apoptosis of vascular smoothmuscle cells is reduced by hmg-coa reductase inhibitor, pravastatin. J AtherosclerThromb,2002,9:65-71
[36] Salonen R, Salonen JT. Carotid atherosclerosis in relation to systolic and diastolic bloodpressure: Kuopio ischaemic heart disease risk factor study. Ann Med,1991,23:23-27
[37] Lloyd-Jones DM, Evans JC, Larson MG, et al. Cross-classification of jnc vi bloodpressure stages and risk groups in the framingham heart study. Arch Intern Med,1999,159:2206-2212
[38] Thomas F, Bean K, Guize L, et al. Combined effects of systolic blood pressure and serumcholesterol on cardiovascular mortality in young (<55years) men and women. Eur HeartJ,2002,23:528-535
[39] Stern N, Grosskopf I, Shapira I, et al. Risk factor clustering in hypertensive patients:Impact of the reports of ncep-ii and second joint task force on coronary prevention onjnc-vi guidelines. J Intern Med,2000,248:203-210
[40] Abbott RD, Rodriguez BL, Petrovitch H, et al. Ankle-brachial blood pressure in elderlymen and the risk of stroke: The honolulu heart program. J Clin Epidemiol,2001,54:973-978
[41] Liao J, Farmer JA. Statins as adjunctive therapy in the management of hypertension. CurrAtheroscler Rep,2010,12:349-354
[42] Goode GK, Miller JP, Heagerty AM. Hyperlipidaemia, hypertension, and coronary heartdisease. Lancet,1995,345:362-364
[43] Sung BH, Izzo JL, Jr., Wilson MF. Effects of cholesterol reduction on bp response tomental stress in patients with high cholesterol. Am J Hypertens,1997,10:592-599
[44] Straznicky NE, Howes LG, Lam W, et al. Effects of pravastatin on cardiovascularreactivity to norepinephrine and angiotensin ii in patients with hypercholesterolemia andsystemic hypertension. Am J Cardiol,1995,75:582-586
[45] Jarai Z, Kapocsi J, Farsang C, et al. Effect of fluvastatin on serum lipid levels in essentialhypertension. Orv Hetil,1996,137:1857-1859
[46] Laufs U, La Fata V, Plutzky J, et al. Upregulation of endothelial nitric oxide synthase byhmg coa reductase inhibitors. Circulation,1998,97:1129-1135
[47] Abetel G, Poget PN, Bonnabry JP. Hypotensive effect of an inhibitor of cholesterolsynthesis (fluvastatin). A pilot study. Schweiz Med Wochenschr,1998,128:272-277
[48] Borghi C, Prandin MG, Costa FV, et al. Use of statins and blood pressure control intreated hypertensive patients with hypercholesterolemia. J Cardiovasc Pharmacol,2000,35:549-555
[49] Glorioso N, Troffa C, Filigheddu F, et al. Effect of the hmg-coa reductase inhibitors onblood pressure in patients with essential hypertension and primary hypercholesterolemia.Hypertension,1999,34:1281-1286
[50] King DE, Mainous AG,3rd, Egan BM, et al. Use of statins and blood pressure. Am JHypertens,2007,20:937-941
[51] Strazzullo P, Kerry SM, Barbato A, et al. Do statins reduce blood pressure?: Ameta-analysis of randomized, controlled trials. Hypertension,2007,49:792-798
[52] Kostapanos MS, Milionis HJ, Elisaf MS. Current role of statins in the treatment ofessential hypertension. Expert Opin Pharmacother,2010,11:2635-2650
[53] Reckless JP. Cholesterol metabolism in arterial smooth muscle and endothelium.Biochem Soc Trans,1978,6:883-887
[54] Arai Y, Sasaki M, Sakuragawa N. Hypoxic effects on cholesterol metabolism of culturedrat aortic and brain microvascular endothelial cells, and aortic vascular smooth musclecells. Tohoku J Exp Med,1996,180:17-25
[55] Weivoda MM, Hohl RJ. Effects of farnesyl pyrophosphate accumulation on calvarialosteoblast differentiation. Endocrinology,2011,152:3113-3122
[56] Yamada H. Ultrastructure of smooth muscle fibers. Nihon Heikatsukin Gakkai Zasshi,1974,10:113-116
[57] Somlyo AP. Excitation-contraction coupling and the ultrastructure of smooth muscle.Circ Res,1985,57:497-507
[58] Somlyo AP. Cell physiology: Cellular site of calcium regulation. Nature,1984,309:516-517
[59] Somlyo AP, Somlyo AV, Kitazawa T, et al. Ultrastructure, function and composition ofsmooth muscle. Ann Biomed Eng,1983,11:579-588
[60] Calcium channel-blocking drugs: A novel intervention for the treatment of cardiacdisease. Proceedings of the symposium on calcium blocking agents. July25-26,1981,tokyo, japan. Circ Res,1983,52:I1-181
[61] Bond M, Kitazawa T, Somlyo AP, et al. Release and recycling of calcium by thesarcoplasmic reticulum in guinea-pig portal vein smooth muscle. J Physiol,1984,355:677-695
[62] Bond M, Shuman H, Somlyo AP, et al. Total cytoplasmic calcium in relaxed andmaximally contracted rabbit portal vein smooth muscle. J Physiol,1984,357:185-201
[63] Carbone E, Lux HD. A low voltage-activated, fully inactivating ca channel in vertebratesensory neurones. Nature,1984,310:501-502
[64] Bezanilla F, Stefani E. Voltage-dependent gating of ionic channels. Annu Rev BiophysBiomol Struct,1994,23:819-846
[65] Casteels R. Electro-and pharmacomechanical coupling in vascular smooth muscle. Chest,1980,78:150-156
[66] Nowycky MC, Fox AP, Tsien RW. Three types of neuronal calcium channel withdifferent calcium agonist sensitivity. Nature,1985,316:440-443
[67] Akhtar RA, Abdel-Latif AA. Carbachol causes rapid phosphodiesteratic cleavage ofphosphatidylinositol4,5-bisphosphate and accumulation of inositol phosphates in rabbitiris smooth muscle; prazosin inhibits noradrenaline-and ionophore a23187-stimulatedaccumulation of inositol phosphates. Biochem J,1984,224:291-300
[68] Burgess GM, Irvine RF, Berridge MJ, et al. Actions of inositol phosphates on ca2+poolsin guinea-pig hepatocytes. Biochem J,1984,224:741-746
[69] Blaustein MP. Sodium ions, calcium ions, blood pressure regulation, and hypertension: Areassessment and a hypothesis. Am J Physiol,1977,232:C165-173
[70]廖家培.钙离子：进入细胞浆的途径与血管平滑肌收缩机制.生理科学进展,1989,Vol.20:49-52
[71] Streb H, Schulz I. Regulation of cytosolic free ca2+concentration in acinar cells of ratpancreas. Am J Physiol,1983,245:G347-357
[72] Streb H, Irvine RF, Berridge MJ, et al. Release of ca2+from a nonmitochondrialintracellular store in pancreatic acinar cells by inositol-1,4,5-trisphosphate. Nature,1983,306:67-69
[73] Headings VE, Rondell PA. Arterial muscle contraction and potassium movement in vitro.Am J Physiol,1962,202:17-20
[74] Klee CB, Crouch TH, Richman PG. Calmodulin. Annu Rev Biochem,1980,49:489-515
[75] Sobieszek A, Small JV. Regulation of the actin-myosin interaction in vertebrate smoothmuscle: Activation via a myosin light-chain kinase and the effect of tropomyosin. J MolBiol,1977,112:559-576
[76] Adelstein RS, Klee CB. Purification of smooth muscle myosin light-chain kinase.Methods Enzymol,1982,85Pt B:298-308
[77] Adelstein RS. Calmodulin and the regulation of the actin-myosin interaction in smoothmuscle and nonmuscle cells. Cell,1982,30:349-350
[78] Adelstein RS, Pato MD, Sellers JR, et al. Regulation of contractile proteins by reversiblephosphorylation of myosin and myosin kinase. Soc Gen Physiol Ser,1982,37:273-281
[79] Adelstein RS, Sellers JR, Conti MA, et al. Regulation of smooth muscle contractileproteins by calmodulin and cyclic amp. Fed Proc,1982,41:2873-2878
[80] Walsh FS, Doherty P. Factors regulating the expression and function ofcalcium-independent cell adhesion molecules. Curr Opin Cell Biol,1993,5:791-796
[81] Ikebe M, Hartshorne DJ. Conformation-dependent proteolysis of smooth-muscle myosin.J Biol Chem,1984,259:11639-11642
[82] Somlyo AP, Somlyo AV. Signal transduction and regulation in smooth muscle. Nature,1994,372:231-236
[83]成建国,杨光明.动脉血压的形成与影响血压正常值的常见因素.西藏医药杂志,2004, Vol.25:31-34
[84] Hauschka SD. Myocardin. A novel potentiator of srf-mediated transcription in cardiacmuscle. Mol Cell,2001,8:1-2
[85] Wang D, Chang PS, Wang Z, et al. Activation of cardiac gene expression by myocardin,a transcriptional cofactor for serum response factor. Cell,2001,105:851-862
[86] Wang DZ, Li S, Hockemeyer D, et al. Potentiation of serum response factor activity by afamily of myocardin-related transcription factors. Proc Natl Acad Sci U S A,2002,99:14855-14860
[87] Doi H, Iso T, Yamazaki M, et al. Herp1inhibits myocardin-induced vascular smoothmuscle cell differentiation by interfering with srf binding to carg box. ArteriosclerThromb Vasc Biol,2005,25:2328-2334
[88] Li S, Wang DZ, Wang Z, et al. The serum response factor coactivator myocardin isrequired for vascular smooth muscle development. Proc Natl Acad Sci U S A,2003,100:9366-9370
[89] Owens GK, Kumar MS, Wamhoff BR. Molecular regulation of vascular smooth musclecell differentiation in development and disease. Physiol Rev,2004,84:767-801
[90] Yoshida T, Sinha S, Dandre F, et al. Myocardin is a key regulator of carg-dependenttranscription of multiple smooth muscle marker genes. Circ Res,2003,92:856-864
[91] Creemers EE, Sutherland LB, McAnally J, et al. Myocardin is a direct transcriptionaltarget of mef2, tead and foxo proteins during cardiovascular development. Development(Cambridge, England),2006,133:4245-4256
[92] Li S, Chang S, Qi X, et al. Requirement of a myocardin-related transcription factor fordevelopment of mammary myoepithelial cells. Molecular and cellular biology,2006,26:5797-5808
[93] Shore P, Sharrocks AD. The mads-box family of transcription factors. Eur J Biochem,1995,229:1-13
[94] Rensen SS, Niessen PM, Long X, et al. Contribution of serum response factor andmyocardin to transcriptional regulation of smoothelins. Cardiovasc Res,2006,70:136-145
[95] Yoshida T, Kawai-Kowase K, Owens GK. Forced expression of myocardin is notsufficient for induction of smooth muscle differentiation in multipotential embryoniccells. Arterioscler Thromb Vasc Biol,2004,24:1596-1601
[96] Li J, Zhu X, Chen M, et al. Myocardin-related transcription factor b is required in cardiacneural crest for smooth muscle differentiation and cardiovascular development. Proc NatlAcad Sci U S A,2005,102:8916-8921
[97] Goss AM, Tian Y, Cheng L, et al. Wnt2signaling is necessary and sufficient to activatethe airway smooth muscle program in the lung by regulating myocardin/mrtf-b and fgf10expression. Dev Biol,2011,356:541-552
[98] Miano JM. Cardiac-specific gene expression: A handful of factors. J Mol Cell Cardiol,2002,34:1287-1291
[99] Shimokawa H, Takeshita A. Rho-kinase is an important therapeutic target incardiovascular medicine. Arterioscler Thromb Vasc Biol,2005,25:1767-1775
[100] Shirai H, Autieri M, Eguchi S. Small gtp-binding proteins and mitogen-activated proteinkinases as promising therapeutic targets of vascular remodeling. Curr Opin NephrolHypertens,2007,16:111-115
[101] Parsons JT. Integrin-mediated signalling: Regulation by protein tyrosine kinases andsmall gtp-binding proteins. Curr Opin Cell Biol,1996,8:146-152
[102] Wang Y, Zheng XR, Riddick N, et al. Rock isoform regulation of myosin phosphataseand contractility in vascular smooth muscle cells. Circ Res,2009,104:531-540
[103] Zhang W, Du L, Gunst SJ. The effects of the small gtpase rhoa on the muscariniccontraction of airway smooth muscle result from its role in regulating actinpolymerization. Am J Physiol Cell Physiol,2010,299:C298-306
[104] Ogita H, Kunimoto S, Kamioka Y, et al. Epha4-mediated rho activation via vsm-rhogefexpressed specifically in vascular smooth muscle cells. Circ Res,2003,93:23-31
[105] Guilluy C, Eddahibi S, Agard C, et al. Rhoa and rho kinase activation in humanpulmonary hypertension: Role of5-ht signaling. Am J Respir Crit Care Med,2009,179:1151-1158
[106] Loirand G, Guerin P, Pacaud P. Rho kinases in cardiovascular physiology andpathophysiology. Circ Res,2006,98:322-334
[107] Janssen LJ, Tazzeo T, Zuo J, et al. Kcl evokes contraction of airway smooth muscle viaactivation of rhoa and rho-kinase. Am J Physiol Lung Cell Mol Physiol,2004,287:L852-858
[108] Bergdahl A, Persson E, Hellstrand P, et al. Lovastatin induces relaxation and inhibitsl-type ca(2+) current in the rat basilar artery. Pharmacol Toxicol,2003,93:128-134
[109] Wamhoff BR, Bowles DK, McDonald OG, et al. L-type voltage-gated ca2+channelsmodulate expression of smooth muscle differentiation marker genes via a rhokinase/myocardin/srf-dependent mechanism. Circ Res,2004,95:406-414
[110] Lagna G, Ku MM, Nguyen PH, et al. Control of phenotypic plasticity of smooth musclecells by bone morphogenetic protein signaling through the myocardin-relatedtranscription factors. J Biol Chem,2007,282:37244-37255
[111] Fibbi B, Morelli A, Marini M, et al. Atorvastatin but not elocalcitol increases sildenafilresponsiveness in spontaneously hypertensive rats by regulating the rhoa/rock pathway. JAndrol,2008,29:70-84
[112] Liao JK. Effects of statins on3-hydroxy-3-methylglutaryl coenzyme a reductaseinhibition beyond low-density lipoprotein cholesterol. Am J Cardiol,2005,96:24F-33F
[113] Van Aelst L, D'Souza-Schorey C. Rho gtpases and signaling networks. Genes Dev,1997,11:2295-2322
[114] Dharmawardhane S, Bokoch GM. Rho gtpases and leukocyte cytoskeletal regulation.Curr Opin Hematol,1997,4:12-18
[115] Fedoruk LM, Wang H, Conaway MR, et al. Statin therapy improves outcomes aftervalvular heart surgery. Ann Thorac Surg,2008,85:1521-1525; discussion1525-1526
[116] Wang CY, Liu PY, Liao JK. Pleiotropic effects of statin therapy: Molecular mechanismsand clinical results. Trends Mol Med,2008,14:37-44
[117] Hall A. Rho gtpases and the actin cytoskeleton. Science,1998,279:509-514
[118] Mackay DJ, Hall A. Rho gtpases. J Biol Chem,1998,273:20685-20688
[119] Li M, Liu Y, Dutt P, et al. Inhibition of serotonin-induced mitogenesis, migration, anderk mapk nuclear translocation in vascular smooth muscle cells by atorvastatin. Am JPhysiol Lung Cell Mol Physiol,2007,293:L463-471
[120] Chapman RH, Petrilla AA, Berman L, et al. Are high-risk hypertensive patients beingprescribed concomitant statin therapy?: A retrospective cohort study. Am J CardiovascDrugs,2009,9:299-308
[121] Uehata M, Ishizaki T, Satoh H, et al. Calcium sensitization of smooth muscle mediatedby a rho-associated protein kinase in hypertension. Nature,1997,389:990-994
[122] Kureishi Y, Kobayashi S, Amano M, et al. Rho-associated kinase directly inducessmooth muscle contraction through myosin light chain phosphorylation. J Biol Chem,1997,272:12257-12260
[123] Matsuo Y, Kuwabara M, Tanaka-Totoribe N, et al. The defective protein level of myosinlight chain phosphatase (mlcp) in the isolated saphenous vein, as a vascular conduit incoronary artery bypass grafting (cabg), harvested from patients with diabetes mellitus(dm). Biochem Biophys Res Commun,2011,412:323-327
[124] Rattan S.3-hydroxymethyl coenzyme a reductase inhibition attenuates spontaneoussmooth muscle tone via rhoa/rock pathway regulated by rhoa prenylation. Am J PhysiolGastrointest Liver Physiol,2010,298:G962-969
[125] Corsini A, Ferri N, Cortellaro M. Are pleiotropic effects of statins real? Vasc Health RiskManag,2007,3:611-613
[126] Laufs U, Liao JK. Isoprenoid metabolism and the pleiotropic effects of statins. CurrAtheroscler Rep,2003,5:372-378
[127] Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol,2005,45:89-118
[128] Zhou Q, Liao JK. Pleiotropic effects of statins.-basic research and clinical perspectives.Circ J,2010,74:818-826
[129] Ye Y, Hu SJ, Li L. Inhibition of farnesylpyrophosphate synthase prevents angiotensinii-induced hypertrophic responses in rat neonatal cardiomyocytes: Involvement of therhoa/rho kinase pathway. FEBS Lett,2009,583:2997-3003
[130] Katayama M, Kawata M, Yoshida Y, et al. The posttranslationally modified c-terminalstructure of bovine aortic smooth muscle rhoa p21. J Biol Chem,1991,266:12639-12645
[131] Adamson P, Marshall CJ, Hall A, et al. Post-translational modifications of p21rhoproteins. J Biol Chem,1992,267:20033-20038
[132] Zhang FL, Casey PJ. Protein prenylation: Molecular mechanisms and functionalconsequences. Annu Rev Biochem,1996,65:241-269
[133] Turner SJ, Zhuang S, Zhang T, et al. Effects of lovastatin on rho isoform expression,activity, and association with guanine nucleotide dissociation inhibitors. BiochemPharmacol,2008,75:405-413
[134] Ruperez M, Rodrigues-Diez R, Blanco-Colio LM, et al. Hmg-coa reductase inhibitorsdecrease angiotensin ii-induced vascular fibrosis: Role of rhoa/rock and mapk pathways.Hypertension,2007,50:377-383
[135] Seko T, Ito M, Kureishi Y, et al. Activation of rhoa and inhibition of myosin phosphataseas important components in hypertension in vascular smooth muscle. Circ Res,2003,92:411-418
[136] Somlyo AP, Somlyo AV. Ca2+sensitivity of smooth muscle and nonmuscle myosin ii:Modulated by g proteins, kinases, and myosin phosphatase. Physiol Rev,2003,83:1325-1358
[137] Mukai Y, Shimokawa H, Matoba T, et al. Involvement of rho-kinase in hypertensivevascular disease: A novel therapeutic target in hypertension. FASEB J,2001,15:1062-1064
[138] Yang L, Gao YJ, Lee RM. The effects of quinapril and atorvastatin on artery structureand function in adult spontaneously hypertensive rats. Eur J Pharmacol,2005,518:145-151
[139] Noma K, Oyama N, Liao JK. Physiological role of rocks in the cardiovascular system.Am J Physiol Cell Physiol,2006,290:C661-668
[140] Lee S, Pagoria D, Raigrodski A, et al. Effects of combinations of ros scavengers onoxidative DNA damage caused by visible-light-activatedcamphorquinone/n,n-dimethyl-p-toluidine. J Biomed Mater Res B Appl Biomater,2007,83:391-399
[141] Castilho RF, Carvalho-Alves PC, Vercesi AE, et al. Oxidative damage to sarcoplasmicreticulum ca(2+)-pump induced by fe2+/h2o2/ascorbate is not mediated by lipidperoxidation or thiol oxidation and leads to protein fragmentation. Mol Cell Biochem,1996,159:105-114
[142] Herrero A, Portero-Otin M, Bellmunt MJ, et al. Effect of the degree of fatty acidunsaturation of rat heart mitochondria on their rates of h2o2production and lipid andprotein oxidative damage. Mech Ageing Dev,2001,122:427-443
[143] Sotnikova R. Investigation of the mechanisms underlying h2o2-evoked contraction in theisolated rat aorta. Gen Pharmacol,1998,31:115-119
[144] Iesaki T, Okada T, Yamaguchi H, et al. Inhibition of vasoactive amine inducedcontractions of vascular smooth muscle by hydrogen peroxide in rabbit aorta. CardiovascRes,1994,28:963-968
[145] Burke TM, Wolin MS. Hydrogen peroxide elicits pulmonary arterial relaxation andguanylate cyclase activation. Am J Physiol,1987,252:H721-732
[146] Iesaki T, Okada T, Shimada I, et al. Decrease in ca2+sensitivity as a mechanism ofhydrogen peroxide-induced relaxation of rabbit aorta. Cardiovasc Res,1996,31:820-825
[147] Qin S, Chock PB. Implication of phosphatidylinositol3-kinase membrane recruitment inhydrogen peroxide-induced activation of pi3k and akt. Biochemistry,2003,42:2995-3003
[148] Sadidi M, Lentz SI, Feldman EL. Hydrogen peroxide-induced akt phosphorylationregulates bax activation. Biochimie,2009,91:577-585
[149] Faghiri Z, Bazan NG. Pi3k/akt and mtor/p70s6k pathways mediate neuroprotectind1-induced retinal pigment epithelial cell survival during oxidative stress-inducedapoptosis. Exp Eye Res,2010,90:718-725
[150] Hegner B, Lange M, Kusch A, et al. Mtor regulates vascular smooth muscle celldifferentiation from human bone marrow-derived mesenchymal progenitors. ArteriosclerThromb Vasc Biol,2009,29:232-238
[151] Martin KA, Rzucidlo EM, Merenick BL, et al. The mtor/p70s6k1pathway regulatesvascular smooth muscle cell differentiation. Am J Physiol Cell Physiol,2004,286:C507-517
[152] Harrison DE, Strong R, Sharp ZD, et al. Rapamycin fed late in life extends lifespan ingenetically heterogeneous mice. Nature,2009,460:392-395
[153] Sarbassov DD, Ali SM, Sengupta S, et al. Prolonged rapamycin treatment inhibits mtorc2assembly and akt/pkb. Mol Cell,2006,22:159-168
[154] Toschi A, Lee E, Xu L, et al. Regulation of mtorc1and mtorc2complex assembly byphosphatidic acid: Competition with rapamycin. Mol Cell Biol,2009,29:1411-1420
[155] Gibbons JJ, Abraham RT, Yu K. Mammalian target of rapamycin: Discovery ofrapamycin reveals a signaling pathway important for normal and cancer cell growth.Semin Oncol,2009,36Suppl3:S3-S17
[156] Sparks CA, Guertin DA. Targeting mtor: Prospects for mtor complex2inhibitors incancer therapy. Oncogene,2010,29:3733-3744
[157] Huang J, Manning BD. A complex interplay between akt, tsc2and the two mtorcomplexes. Biochem Soc Trans,2009,37:217-222
[158] Wang X, Beugnet A, Murakami M, et al. Distinct signaling events downstream of mtorcooperate to mediate the effects of amino acids and insulin on initiation factor4e-bindingproteins. Mol Cell Biol,2005,25:2558-2572
[159] Cheng SW, Fryer LG, Carling D, et al. Thr2446is a novel mammalian target ofrapamycin (mtor) phosphorylation site regulated by nutrient status. J Biol Chem,2004,279:15719-15722
[160] Asnaghi L, Bruno P, Priulla M, et al. Mtor: A protein kinase switching between life anddeath. Pharmacol Res,2004,50:545-549
[161] O'Shea C, Klupsch K, Choi S, et al. Adenoviral proteins mimic nutrient/growth signals toactivate the mtor pathway for viral replication. EMBO J,2005,24:1211-1221
[162] Jastrzebski K, Hannan KM, Tchoubrieva EB, et al. Coordinate regulation of ribosomebiogenesis and function by the ribosomal protein s6kinase, a key mediator of mtorfunction. Growth Factors,2007,25:209-226
[163] Lucchesi PA. Rapamycin plays a new role as differentiator of vascular smooth musclephenotype. Focus on "the mtor/p70s6k1pathway regulates vascular smooth muscledifferentiation". Am J Physiol Cell Physiol,2004,286:C480-481
[164] Kanda T, Hayashi K, Wakino S, et al. Role of rho-kinase and p27in angiotensinii-induced vascular injury. Hypertension,2005,45:724-729
[165] Yao JS, Chen Y, Zhai W, et al. Minocycline exerts multiple inhibitory effects on vascularendothelial growth factor-induced smooth muscle cell migration: The role of erk1/2, pi3k,and matrix metalloproteinases. Circ Res,2004,95:364-371
[166] Panwalkar A, Verstovsek S, Giles FJ. Mammalian target of rapamycin inhibition astherapy for hematologic malignancies. Cancer,2004,100:657-666
[167] Sarbassov DD, Guertin DA, Ali SM, et al. Phosphorylation and regulation of akt/pkb bythe rictor-mtor complex. Science,2005,307:1098-1101
[168] Fraga D, Sehring IM, Kissmehl R, et al. Protein phosphatase2b (pp2b, calcineurin) inparamecium: Partial characterization reveals that two members of the unusually largecatalytic subunit family have distinct roles in calcium dependent processes. Eukaryot Cell,2010,
[169] Roberts-Wilson TK, Reddy RN, Bailey JL, et al. Calcineurin signaling and pgc-1alphaexpression are suppressed during muscle atrophy due to diabetes. Biochim Biophys Acta,2010,
[170] Mackiewicz U, Maczewski M, Klemenska E, et al. Brief postinfarction calcineurinblockade affects left ventricular remodeling and ca2+handling in the rat. J Mol CellCardiol,2010,48:1307-1315
[171] Kubokawa M, Kojo T, Komagiri Y, et al. Role of calcineurin-mediateddephosphorylation in modulation of an inwardly rectifying k+channel in humanproximal tubule cells. J Membr Biol,2009,231:79-92
[172] Mallinson J, Meissner J, Chang KC. Chapter2. Calcineurin signaling and the slowoxidative skeletal muscle fiber type. Int Rev Cell Mol Biol,2009,277:67-101
[173] Dallas A, Khalil RA. Ca2+antagonist-insensitive coronary smooth muscle contractioninvolves activation of epsilon-protein kinase c-dependent pathway. Am J Physiol CellPhysiol,2003,285:C1454-1463
[174] Ghosh R, Emmons SW. Calcineurin and protein kinase g regulate c. Elegans behavioralquiescence during locomotion in liquid. BMC Genet,2010,11:7
[175] Yamashiro T, Kuge H, Zhang J, et al. Calcineurin mediates the angiotensin ii-inducedaldosterone synthesis in the adrenal glands by upregulation of transcription of thecyp11b2gene. J Biochem,2010,
[176] Mano A, Tatsumi T, Shiraishi J, et al. Aldosterone directly induces myocyte apoptosisthrough calcineurin-dependent pathways. Circulation,2004,110:317-323
[177] Tumlin JA, Lea JP, Swanson CE, et al. Aldosterone and dexamethasone stimulatecalcineurin activity through a transcription-independent mechanism involving steroidreceptor-associated heat shock proteins. J Clin Invest,1997,99:1217-1223
[178] Martin-Garrido A, Gonzalez-Ramos M, Griera M, et al. H2o2regulation of vascularfunction through sgc mrna stabilization by hur. Arterioscler Thromb Vasc Biol,2011,31:567-573
[179] Xiao Q, Luo Z, Pepe AE, et al. Embryonic stem cell differentiation into smooth musclecells is mediated by nox4-produced h2o2. Am J Physiol Cell Physiol,2009,296:C711-723
[180] Cascino T, Csanyi G, Al Ghouleh I, et al. Adventitia-derived hydrogen peroxide impairsrelaxation of the rat carotid artery via smooth muscle cell p38mitogen-activated proteinkinase. Antioxid Redox Signal,2011,15:1507-1515
[181] Uetz P, Giot L, Cagney G, et al. A comprehensive analysis of protein-protein interactionsin saccharomyces cerevisiae. Nature,2000,403:623-627
[182] Mulet JM, Martin DE, Loewith R, et al. Mutual antagonism of target of rapamycin andcalcineurin signaling. J Biol Chem,2006,281:33000-33007
[183] Byon CH, Javed A, Dai Q, et al. Oxidative stress induces vascular calcification throughmodulation of the osteogenic transcription factor runx2by akt signaling. J Biol Chem,2008,283:15319-15327
[184] Radisavljevic ZM, Gonzalez-Flecha B. Tor kinase and ran are downstream from pi3k/aktin h2o2-induced mitosis. J Cell Biochem,2004,91:1293-1300
[185] Desai BN, Myers BR, Schreiber SL. Fkbp12-rapamycin-associated protein associateswith mitochondria and senses osmotic stress via mitochondrial dysfunction. Proc NatlAcad Sci U S A,2002,99:4319-4324
[186] Ikenoue T, Inoki K, Yang Q, et al. Essential function of torc2in pkc and akt turn motifphosphorylation, maturation and signalling. EMBO J,2008,27:1919-1931
[187] Tocci MJ, Sigal NH. Recent advances in the mechanism of action of cyclosporine andfk506. Curr Opin Nephrol Hypertens,1992,1:236-242
[188] Leblanc N, Ledoux J, Saleh S, et al. Regulation of calcium-activated chloride channels insmooth muscle cells: A complex picture is emerging. Can J Physiol Pharmacol,2005,83:541-556
[189] Ledoux J, Greenwood I, Villeneuve LR, et al. Modulation of ca2+-dependent cl-channels by calcineurin in rabbit coronary arterial myocytes. J Physiol,2003,552:701-714
[190] Cameron AM, Nucifora FC, Jr., Fung ET, et al. Fkbp12binds the inositol1,4,5-trisphosphate receptor at leucine-proline (1400-1401) and anchors calcineurin tothis fk506-like domain. J Biol Chem,1997,272:27582-27588
[191] Cameron AM, Steiner JP, Sabatini DM, et al. Immunophilin fk506binding proteinassociated with inositol1,4,5-trisphosphate receptor modulates calcium flux. Proc NatlAcad Sci U S A,1995,92:1784-1788
[192] Dargan SL, Lea EJ, Dawson AP. Modulation of type-1ins(1,4,5)p3receptor channels bythe fk506-binding protein, fkbp12. Biochem J,2002,361:401-407
[193] Jahnke T, Schafer FK, Bolte H, et al. Short-term rapamycin for inhibition of neointimaformation after balloon-mediated aortic injury in rats: Is there a window of opportunityfor systemic prophylaxis of restenosis? J Endovasc Ther,2005,12:332-342
[194] Lee KJ, Hinek A, Chaturvedi RR, et al. Rapamycin-eluting stents in the arterial duct:Experimental observations in the pig model. Circulation,2009,119:2078-2085
[195] Hilker M, Buerke M, Guckenbiehl M, et al. Rapamycin reduces neointima formationduring vascular injury. Vasa,2003,32:10-13
[196] Kwon YS, Hong HS, Kim JC, et al. Inhibitory effect of rapamycin on cornealneovascularization in vitro and in vivo. Invest Ophthalmol Vis Sci,2005,46:454-460
[197] Pan M, de Lezo JS, Medina A, et al. Rapamycin-eluting stents for the treatment ofbifurcated coronary lesions: A randomized comparison of a simple versus complexstrategy. Am Heart J,2004,148:857-864
[198] Neto Mde M, Di Marco GS, Casarini DE, et al. Orally administered rapamycin does notmodify rat aortic vascular tone. J Cardiovasc Pharmacol,2007,49:96-99
[199] Antoniades C, Bakogiannis C, Tousoulis D, et al. Preoperative atorvastatin treatment incabg patients rapidly improves vein graft redox state by inhibition of rac1andnadph-oxidase activity. Circulation,2010,122:S66-73
[200] Carnevale R, Pignatelli P, Di Santo S, et al. Atorvastatin inhibits oxidative stress viaadiponectin-mediated nadph oxidase down-regulation in hypercholesterolemic patients.Atherosclerosis,2010,213:225-234
[201] Chiu CZ, Wang BW, Shyu KG. Use of atorvastatin to inhibit hypoxia-induced myocardinexpression. Eur J Clin Invest,2012,42:564-571
[202] Finlay GA, Malhowski AJ, Liu Y, et al. Selective inhibition of growth of tuberoussclerosis complex2null cells by atorvastatin is associated with impaired rheb and rhogtpase function and reduced mtor/s6kinase activity. Cancer Res,2007,67:9878-9886