雌激素抗衰老的SIRT1蛋白机制研究
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摘要
第一部分雌激素抗衰老的SIRT1蛋白机制研究
研究目的:衰老被认为是随时间而逐渐出现的机体器官功能和应激反应衰退并伴有发病率和死亡率增加的一个现象。衰老也被认为是心脑血管疾病等重要疾病的独立危险因素。目前认为衰老的病理机制主要是随年龄增长机体损伤的积累所致。如细胞内蛋白质、脂类和DNA等大分子不断受到外源性或内源性刺激而导致损伤。外源性的损伤包括紫外线的照射及环境中有毒物质的损害,而内源性的刺激主要是反应氧族(reactive oxygen species,ROS)诱发的氧化应激的损伤作用。除了氧化应激在衰老机制中得到普遍共识外,还存在其他多种学说,如细胞凋亡率增加、染色体末端端粒逐渐变短、线粒体DNA突变率增加和累积、DNA甲基化水平的降低、免疫系统功能失调、体内干细胞数量的减少和功能的减退及女性更年期后雌激素分泌水平的降低等等。虽然目前存在多种学说解释衰老的发生,但是对于确切的机制及衰老是否受基因调控等问题,目前还不清楚。近年来,很多学者注意到当热量限制后,从真菌、线虫、果蝇甚至小鼠等动物的寿命均可明显延长,并且这种作用和组蛋白去乙酰化酶-sirtuin蛋白家族有关。Sir2是一种依赖NAD~+的组蛋白去乙酰化酶。最先引发研究者兴趣的是,当过表达Sir2蛋白后,细胞组蛋白乙酰化的水平降低并且在酵母和多细胞生物还发现寿命延长的现象。另外,用Sir2的激动剂如白藜芦醇刺激酵母后,酵母的寿命也能明显延长,而且在线虫和果蝇甚至小鼠也能观察到这一现象。如果将Sir2基因突变或者用药物阻断Sir2后发现酵母的衰老过程是加速的。Sir2家族蛋白不仅调节组蛋白乙酰化的水平,还可调节多种转录调节蛋白、基因沉默、DNA修复以及细胞周期等因素以调控衰老的过程。Sir2在哺乳动物中被称为SIRT1。SIRT1能够将p53、Ku70及FOXO(forkhead box class O)去乙酰化从而抑制细胞凋亡;SIRT1还可通过增加hTERT的表达抑制端粒缩短;在白色脂肪细胞中SIRT1可阻断核受体PPAR-γ达到抑制脂肪蓄积的作用。可见SIRT1能够通过多种途径发挥抗衰老的作用。
哺乳动物中雌性的寿命长于雄性已达到共识。雌性Wistar大鼠平均寿命比雄性Wistar大鼠寿命长14%。在人类中,男性的平均寿命也比女性的平均寿命短。这个现象也告诉我们,性别之间寿命的差异不仅是社会背景的区别,更重要的是由性别之间生物学的差异造成的。进一步对Wistar大鼠的研究发现,雌性Wistar大鼠产生的ROS要比雄性产生的量少。研究者认为雌激素可能通过减少氧化应激增加抗氧化功能进而发挥抗衰老作用。表明雌激素在女性抗衰老中起到非常重要的作用。但雌激素是否也调节SIRT1的活动,雌激素和热量限制之间有何关系,目前还未发现相关的研究报道。
研究方法:本课题利用体外培养的血管平滑肌细胞、大鼠去卵巢模型、Western Blot、免疫细胞化学、放射免疫学检测、大鼠全基因组分析等方法进一步研究雌激素的抗衰老作用机制。
实验结果:
1.体外培养大鼠胸主动脉平滑肌细胞,用17β-estradiol(10~(-9)-10~(-6)M)刺激细胞24h,提取细胞核蛋白,发现SIRT1蛋白表达明显增高,并与雌二醇的加样量呈剂量依赖效应。雌激素受体ERa的阻断剂能够明显抑制雌激素的效应。雌激素受体ERa的激动剂也能促进SIRT1蛋白的表达,ERβ的激动剂对SIRT1蛋白的表达无明显作用。
2.制备大鼠卵巢切除动物模型组,假手术和卵巢切除后补充外源性的17β-estradiol的模型组。动物饲养4个月。提取脑、左心室、主动脉、肝脏、肾脏和后肢骨骼肌的蛋白。发现卵巢切除的大鼠各组织器官的SIRT1蛋白表达均比假手术组表达低,而卵巢切除的大鼠经雌二醇替代治疗后SIRT1蛋白表达几乎和假手术组表达相同。
3.制备大鼠卵巢切除加限食模型:(1)假手术组;(2)假手术组+60%限食;(3)大鼠卵巢切除动物模型组;(4)大鼠卵巢切除动物模型组+60%限食。动物饲养4个月。限食后大鼠血清胰岛素的含量均比正常饮食组低,而动物组织器官的SIRT1蛋白表达比正常饮食组表达高。在假手术组中,限食对动物血清中雌激素的水平无明显影响;在卵巢切除组,限食后动物雌激素和孕酮在血清中的含量明显增高。并且多种组织中SIRT1蛋白和ERa的表达也明显增加。
4.取卵巢切除和假手术组动物血清刺激平滑肌细胞48h,卵巢切除动物血清刺激后的细胞SIRT1蛋白表达明显降低。进一步用27K Rat Genome Array共有约26962条的全基因组基因芯片,研究这两种血清对细胞刺激48h后基因表达的差异。结果显示共有397点差异表达的基因,其中已知功能的187个基因中,大致可分为5大类:代谢相关的酶;细胞应激相关的信号分子;氧化还原反应相关的分子;钙钾离子通道;细胞凋亡相关分子等分子。实验结果进一步表明卵巢切除后细胞应激性抵抗减弱可能与细胞能量水平降低、氧化应激水平增高、细胞内离子梯度失调及细胞凋亡增加等因素相关。
结论:
1.雌激素能够明显促进SIRT1蛋白的表达,并且雌激素的这一作用是通过ERa介导的。
2.雌性大鼠中SIRT1蛋白的表达可能很大程度上依赖于雌激素的作用,尤其是在心血管系统。
3.雌性动物中限食的部分保护作用可能是通过雌激素的活动实现的,当卵巢切除后,机体在雌激素水平减少的情况下,能够增加卵巢外的激素合成的代偿途径及雌激素受体的表达,来加强雌激素介导的限食保护作用。
4.基因芯片结果提示,抑制平滑肌细胞内脂类和胆固醇过度合成、保持线粒体功能的稳定、完善细胞抗氧化能力、增强细胞修复功能及维护细胞内离子稳态等是可能女性抗衰老的重要机制。
第二部分丹参酮ⅡA磺酸钠保护缺血性心肌损伤的机制研究
心肌细胞凋亡是心血管疾病的独立危险因素。研究表明反应氧族(reactive oxygenspecies,ROS)能够诱发心肌细胞凋亡,并可激活促进细胞凋亡的因子,如参与应激反应的丝裂原激活蛋白激酶(mitogen-activated protein kinases,MAPKs),其中JNK/SAPK(c-Jun N-terminal kinases/stress-activated protein kinases)和p38 MAPK在诱发心肌细胞凋亡中起重要作用。丹参酮ⅡA磺酸钠(Sodium tanshinoneⅡAsulfonate,STS)是丹参酮ⅡA经磺化后得到的一种水溶性钠盐。丹参是中国传统中药广泛用于治疗心血管疾病的药品。研究显示STS能够抑制线粒体内氧自由基的形成从而改善缺血再灌注损伤。但对于STS由氧化应激诱发的心肌细胞凋亡的研究还很少。本课题应用大鼠心肌梗死模型和体外培养的心肌细胞氧化应激模型来研究STS对心肌的保护作用。研究发现,STS能够明显减少大鼠心肌梗死模型的心肌梗死区比例,并且降低血清乳酸脱氢酶的水平。进一步发现STS可减少心脏梗死区凋亡的心肌细胞数量。在体外培养心肌细胞实验中,发现STS能显著提高过氧化氢刺激导致的细胞活力的降低。用TUNEL标记法显示过氧化氢能明显增加心肌细胞凋亡数量,而STS能抑制过氧化氢的这一损伤作用。进一步机制研究发现过氧化氢刺激心肌细胞后,JNK和p38 MAPK被激活,这可能与诱发细胞凋亡有关。而STS能够明显抑制由过氧化氢导致的JNK的激活作用,但对p38 MAPK的激活无明显作用。我们认为STS对氧化应激诱发的心肌细胞损伤有保护作用,并能减少心肌细胞凋亡的发生率,这一作用可能和阻断氧化应激诱发的JNK的激活作用有关。
The role of SIRT1 protein in anti-aging effects of estrogen
Aging is defined by the loss of functional reserve over time, leading to a decreased capacity to maintain homeostasis under stress and increased risk of morbidity and mortality. Aging is extremely heterogenerous between individuals and even between tissues within an organism, making it challenging to identify the molecular basis of ageing. Many studies revealed not only causes of aging, but also signaling mechanisms that both promote and protect against ageing. In all cases, the signaling pathways that influence life span are familiar mechanisms that regulate cellular metabolism, growth, proliferation, differentiation and survival. Aging is associated with a progressive imbalance between antioxidant defenses and intracellular concentrations of reactive oxygen species (ROS) as exemplified by increases in products of lipid peroxidation, protein oxidation, and DNA oxidation. Evidence shows that lifespan extension in laboratory yeast, flies and rats maintained on a caloric restriction (CR) diet. CR reduces metabolic rate and oxidative damage. In yeast, reduction in glucose levels in the media, mimicking CR, results in a substantial extension in lifespan, which is Sir2p- and NAD~+-dependent, since mutants for Sir2p and nicotinate phosphoribosyl transferase , an enzyme required for NAD~+ formation, failed to reproduce this effect. Sir2 belongs to the third class of histone deacetylases. Most interesting was the fact that overexpression of the gene encoding the Sir2 protein leads to a decrease in histone acetylation and an increase in life span in yeast, in the menatode Caenorhabditis elegans and in metazoans. Likewise, Sir2-activating compounds such as resveratrol promote longevity in yeast and other organisms ranging from the worm and drosophila to the mouse. On the other hand, both mutations of the Sir2 gene and pharmacological inhibition of Sir2 protein by nicotinamide induce an acceleration of aging in yeast. Since the Sir2 family of proteins are also able to exert their enzymatic activity not only on histones but also on numerous other proteins, such as the transcriptional regulators, they are involved in many cellular processes, ranging from gene silencing, DNA repair, progression of the cell cycle, to the control of aging. SIRT1, the mammalian Sir2 ortholog, controls lifespan extension under CR conditions.
Females live longer than males in many mammalian species. Female Wistar rat median life span is 29 months, 14% more than in male Wistar rats. In Europe, the average life span is 73.7 years for males and 83.8 years for females. The fact that this differences occurs in animals as well as in humans, indicated that the difference cannot be attributed to sociological differences but rather to specific biological characteristics of both genders. Mitochondria from females produce approximately half the amount of hydrogen peroxide than males. Females behave as double transgenics overexpressing both superoxide dismutase and glutathione peroxidase. This is due to estrogen that acts by binding to the estrogen receptors and subsequently activating the mitogen activated protein kinase and nuclear factor kappa B signaling pathways. In addition, estrogen increases antiapoptotic proteins, which prevents activation of the permeability transition pore protection against estrogen-induced increase in mitochondrial Ca~(2+) sequestration. However, little is known about the relationship belong estrogen, SIRT1 and CR. To further understand the role of SIRT1 in anti-aging effects mediated by estrogen in cardiovascular system. In this project, we used primary vascular smooth muscle cells, ovary ectomized rats, CR rats and rat genome microarrays to investigate this mechanism.
The main results of this project are as follows:
1. Primary vascular smooth muscle cells were isolated from aortic arteries in female SD rats. Exposure cells to different concentration of 178-estradiol (10~(-9)-10~(-5)M), we found that 178-estradiol increased the SIRT1 protein expression, which was dosage-dependent. Antagonists of ERa and ERβblocked the increasing effects induced by 176-estradiol. We further used agonists of ERa and ERβto stimulated cultured cells. Results shown that agonist of ERa enhanced SIRT1 protein expression but agonist of ERβhad no this effect.
2. We used ovary ectomized rats to study effects of 17B-estradiol on SIRT1. Three groups rats in this experiment including Sham group, ovary ectomized rats and ovary ectomized rats with exogenous 17β-estradiol treatment. All rats were kept for 4 months. Then we isolated brains, hearts, aortic arteries, livers, kidney and skeletal muscles, which were quickly put in liquid nitrogen. We detected SIRT1 in these tissues and found that protein expression of SIRT1 decreased in ovary ectomized rats in comparison with Sham group. Exogenous 17B-estradiol treatment reversed the decreased SIRT1 protein expression.
3. We further used 4 groups in this branch experiments. (1) Sham group; (2) Sham group+CR; (3) ovary ectomized rats; (4) ovary ectomized rats+CR. Totally insulin levels in serum decreased and SIRT1 protein in tissues increased in CR groups. No differences of serum estradiol were found between Sham group and Sham group+CR group. The serum estradiol and progesterone levels significantly increased in ovary ectomized rats+CR compared with ovary ectomized rats. The protein expression of SIRT1 and ERa significantly increased in CR groups.
4. Exposure cultured VSMC to serum from Sham rats and ovary ectomized rats for 48h. We found that SIRT1 protein decreased in cells stimulated by serum from ovary ectomized rats in comparison with Sham rats. We further used rat genome microarrays to identify different gene expression in cells stimulated different serum from Sham rats and ovary ectomized rats for 48h. Our data indicated that 400 genes changed between two groups including metabolic enzymes, stress-related proteins, signal transduction proteins, calcium and potassium ion channels and apoptotic related genes.
The cardioprotective effects of sodium tanshinoneⅡA sulfonate against ischemia-induced injury in rat hearts
Sodium tanshinoneⅡA sulfonate (STS) is a water soluble derivative of tanshinoneⅡA, a well-known Chinese medicine for treating cardiovascular disorders. Cardiomyocyte apoptosis plays a major role in the development of cardiovascular diseases. The present study was designed to investigate the effects of STS on cardiomyocyte apoptosis induced both by in vivo acute myocardial infarction (MI) in adult rats and by in vitro H_2O_2-treated neonatal rat ventricular myocytes. In MI rats, STS significantly reduced the infarct sizes, the blood lactate dehydrogenase (LDH) level and the number of apoptotic cardiomyocytes in the infarcted hearts. In the in vitro study, STS reversed the decreased effect of cell viability induced by H_2O_2. In addition, STS also markedly inhibited H_2O_2-induced cardiomyocyte apoptosis. C-Jun N-terminal kinases/stress-activated protein kinases (JNKs/SAPKs) and p38 MAPK are classic oxidative stress-activated protein kinases. Our further mechanistic study revealed that increased JNK phosphorylation stimulated by H_2O_2 was abolished by STS treatment. In conclusion, inhibition of JNK activation plays a significant role in cardioprotective effects of STS.
研究目的:衰老被认为是随时间而逐渐出现的机体器官功能和应激反应衰退并伴有发病率和死亡率增加的一个现象。衰老也被认为是心脑血管疾病等重要疾病的独立危险因素。目前认为衰老的病理机制主要是随年龄增长机体损伤的积累所致。如细胞内蛋白质、脂类和DNA等大分子不断受到外源性或内源性刺激而导致损伤。外源性的损伤包括紫外线的照射及环境中有毒物质的损害,而内源性的刺激主要是反应氧族(reactive oxygen species,ROS)诱发的氧化应激的损伤作用。除了氧化应激在衰老机制中得到普遍共识外,还存在其他多种学说,如细胞凋亡率增加、染色体末端端粒逐渐变短、线粒体DNA突变率增加和累积、DNA甲基化水平的降低、免疫系统功能失调、体内干细胞数量的减少和功能的减退及女性更年期后雌激素分泌水平的降低等等。虽然目前存在多种学说解释衰老的发生,但是对于确切的机制及衰老是否受基因调控等问题,目前还不清楚。近年来,很多学者注意到当热量限制后,从真菌、线虫、果蝇甚至小鼠等动物的寿命均可明显延长,并且这种作用和组蛋白去乙酰化酶-sirtuin蛋白家族有关。Sir2是一种依赖NAD~+的组蛋白去乙酰化酶。最先引发研究者兴趣的是,当过表达Sir2蛋白后,细胞组蛋白乙酰化的水平降低并且在酵母和多细胞生物还发现寿命延长的现象。另外,用Sir2的激动剂如白藜芦醇刺激酵母后,酵母的寿命也能明显延长,而且在线虫和果蝇甚至小鼠也能观察到这一现象。如果将Sir2基因突变或者用药物阻断Sir2后发现酵母的衰老过程是加速的。Sir2家族蛋白不仅调节组蛋白乙酰化的水平,还可调节多种转录调节蛋白、基因沉默、DNA修复以及细胞周期等因素以调控衰老的过程。Sir2在哺乳动物中被称为SIRT1。SIRT1能够将p53、Ku70及FOXO(forkhead box class O)去乙酰化从而抑制细胞凋亡;SIRT1还可通过增加hTERT的表达抑制端粒缩短;在白色脂肪细胞中SIRT1可阻断核受体PPAR-γ达到抑制脂肪蓄积的作用。可见SIRT1能够通过多种途径发挥抗衰老的作用。
哺乳动物中雌性的寿命长于雄性已达到共识。雌性Wistar大鼠平均寿命比雄性Wistar大鼠寿命长14%。在人类中,男性的平均寿命也比女性的平均寿命短。这个现象也告诉我们,性别之间寿命的差异不仅是社会背景的区别,更重要的是由性别之间生物学的差异造成的。进一步对Wistar大鼠的研究发现,雌性Wistar大鼠产生的ROS要比雄性产生的量少。研究者认为雌激素可能通过减少氧化应激增加抗氧化功能进而发挥抗衰老作用。表明雌激素在女性抗衰老中起到非常重要的作用。但雌激素是否也调节SIRT1的活动,雌激素和热量限制之间有何关系,目前还未发现相关的研究报道。
研究方法:本课题利用体外培养的血管平滑肌细胞、大鼠去卵巢模型、Western Blot、免疫细胞化学、放射免疫学检测、大鼠全基因组分析等方法进一步研究雌激素的抗衰老作用机制。
实验结果:
1.体外培养大鼠胸主动脉平滑肌细胞,用17β-estradiol(10~(-9)-10~(-6)M)刺激细胞24h,提取细胞核蛋白,发现SIRT1蛋白表达明显增高,并与雌二醇的加样量呈剂量依赖效应。雌激素受体ERa的阻断剂能够明显抑制雌激素的效应。雌激素受体ERa的激动剂也能促进SIRT1蛋白的表达,ERβ的激动剂对SIRT1蛋白的表达无明显作用。
2.制备大鼠卵巢切除动物模型组,假手术和卵巢切除后补充外源性的17β-estradiol的模型组。动物饲养4个月。提取脑、左心室、主动脉、肝脏、肾脏和后肢骨骼肌的蛋白。发现卵巢切除的大鼠各组织器官的SIRT1蛋白表达均比假手术组表达低,而卵巢切除的大鼠经雌二醇替代治疗后SIRT1蛋白表达几乎和假手术组表达相同。
3.制备大鼠卵巢切除加限食模型:(1)假手术组;(2)假手术组+60%限食;(3)大鼠卵巢切除动物模型组;(4)大鼠卵巢切除动物模型组+60%限食。动物饲养4个月。限食后大鼠血清胰岛素的含量均比正常饮食组低,而动物组织器官的SIRT1蛋白表达比正常饮食组表达高。在假手术组中,限食对动物血清中雌激素的水平无明显影响;在卵巢切除组,限食后动物雌激素和孕酮在血清中的含量明显增高。并且多种组织中SIRT1蛋白和ERa的表达也明显增加。
4.取卵巢切除和假手术组动物血清刺激平滑肌细胞48h,卵巢切除动物血清刺激后的细胞SIRT1蛋白表达明显降低。进一步用27K Rat Genome Array共有约26962条的全基因组基因芯片,研究这两种血清对细胞刺激48h后基因表达的差异。结果显示共有397点差异表达的基因,其中已知功能的187个基因中,大致可分为5大类:代谢相关的酶;细胞应激相关的信号分子;氧化还原反应相关的分子;钙钾离子通道;细胞凋亡相关分子等分子。实验结果进一步表明卵巢切除后细胞应激性抵抗减弱可能与细胞能量水平降低、氧化应激水平增高、细胞内离子梯度失调及细胞凋亡增加等因素相关。
结论:
1.雌激素能够明显促进SIRT1蛋白的表达,并且雌激素的这一作用是通过ERa介导的。
2.雌性大鼠中SIRT1蛋白的表达可能很大程度上依赖于雌激素的作用,尤其是在心血管系统。
3.雌性动物中限食的部分保护作用可能是通过雌激素的活动实现的,当卵巢切除后,机体在雌激素水平减少的情况下,能够增加卵巢外的激素合成的代偿途径及雌激素受体的表达,来加强雌激素介导的限食保护作用。
4.基因芯片结果提示,抑制平滑肌细胞内脂类和胆固醇过度合成、保持线粒体功能的稳定、完善细胞抗氧化能力、增强细胞修复功能及维护细胞内离子稳态等是可能女性抗衰老的重要机制。
第二部分丹参酮ⅡA磺酸钠保护缺血性心肌损伤的机制研究
心肌细胞凋亡是心血管疾病的独立危险因素。研究表明反应氧族(reactive oxygenspecies,ROS)能够诱发心肌细胞凋亡,并可激活促进细胞凋亡的因子,如参与应激反应的丝裂原激活蛋白激酶(mitogen-activated protein kinases,MAPKs),其中JNK/SAPK(c-Jun N-terminal kinases/stress-activated protein kinases)和p38 MAPK在诱发心肌细胞凋亡中起重要作用。丹参酮ⅡA磺酸钠(Sodium tanshinoneⅡAsulfonate,STS)是丹参酮ⅡA经磺化后得到的一种水溶性钠盐。丹参是中国传统中药广泛用于治疗心血管疾病的药品。研究显示STS能够抑制线粒体内氧自由基的形成从而改善缺血再灌注损伤。但对于STS由氧化应激诱发的心肌细胞凋亡的研究还很少。本课题应用大鼠心肌梗死模型和体外培养的心肌细胞氧化应激模型来研究STS对心肌的保护作用。研究发现,STS能够明显减少大鼠心肌梗死模型的心肌梗死区比例,并且降低血清乳酸脱氢酶的水平。进一步发现STS可减少心脏梗死区凋亡的心肌细胞数量。在体外培养心肌细胞实验中,发现STS能显著提高过氧化氢刺激导致的细胞活力的降低。用TUNEL标记法显示过氧化氢能明显增加心肌细胞凋亡数量,而STS能抑制过氧化氢的这一损伤作用。进一步机制研究发现过氧化氢刺激心肌细胞后,JNK和p38 MAPK被激活,这可能与诱发细胞凋亡有关。而STS能够明显抑制由过氧化氢导致的JNK的激活作用,但对p38 MAPK的激活无明显作用。我们认为STS对氧化应激诱发的心肌细胞损伤有保护作用,并能减少心肌细胞凋亡的发生率,这一作用可能和阻断氧化应激诱发的JNK的激活作用有关。
The role of SIRT1 protein in anti-aging effects of estrogen
Aging is defined by the loss of functional reserve over time, leading to a decreased capacity to maintain homeostasis under stress and increased risk of morbidity and mortality. Aging is extremely heterogenerous between individuals and even between tissues within an organism, making it challenging to identify the molecular basis of ageing. Many studies revealed not only causes of aging, but also signaling mechanisms that both promote and protect against ageing. In all cases, the signaling pathways that influence life span are familiar mechanisms that regulate cellular metabolism, growth, proliferation, differentiation and survival. Aging is associated with a progressive imbalance between antioxidant defenses and intracellular concentrations of reactive oxygen species (ROS) as exemplified by increases in products of lipid peroxidation, protein oxidation, and DNA oxidation. Evidence shows that lifespan extension in laboratory yeast, flies and rats maintained on a caloric restriction (CR) diet. CR reduces metabolic rate and oxidative damage. In yeast, reduction in glucose levels in the media, mimicking CR, results in a substantial extension in lifespan, which is Sir2p- and NAD~+-dependent, since mutants for Sir2p and nicotinate phosphoribosyl transferase , an enzyme required for NAD~+ formation, failed to reproduce this effect. Sir2 belongs to the third class of histone deacetylases. Most interesting was the fact that overexpression of the gene encoding the Sir2 protein leads to a decrease in histone acetylation and an increase in life span in yeast, in the menatode Caenorhabditis elegans and in metazoans. Likewise, Sir2-activating compounds such as resveratrol promote longevity in yeast and other organisms ranging from the worm and drosophila to the mouse. On the other hand, both mutations of the Sir2 gene and pharmacological inhibition of Sir2 protein by nicotinamide induce an acceleration of aging in yeast. Since the Sir2 family of proteins are also able to exert their enzymatic activity not only on histones but also on numerous other proteins, such as the transcriptional regulators, they are involved in many cellular processes, ranging from gene silencing, DNA repair, progression of the cell cycle, to the control of aging. SIRT1, the mammalian Sir2 ortholog, controls lifespan extension under CR conditions.
Females live longer than males in many mammalian species. Female Wistar rat median life span is 29 months, 14% more than in male Wistar rats. In Europe, the average life span is 73.7 years for males and 83.8 years for females. The fact that this differences occurs in animals as well as in humans, indicated that the difference cannot be attributed to sociological differences but rather to specific biological characteristics of both genders. Mitochondria from females produce approximately half the amount of hydrogen peroxide than males. Females behave as double transgenics overexpressing both superoxide dismutase and glutathione peroxidase. This is due to estrogen that acts by binding to the estrogen receptors and subsequently activating the mitogen activated protein kinase and nuclear factor kappa B signaling pathways. In addition, estrogen increases antiapoptotic proteins, which prevents activation of the permeability transition pore protection against estrogen-induced increase in mitochondrial Ca~(2+) sequestration. However, little is known about the relationship belong estrogen, SIRT1 and CR. To further understand the role of SIRT1 in anti-aging effects mediated by estrogen in cardiovascular system. In this project, we used primary vascular smooth muscle cells, ovary ectomized rats, CR rats and rat genome microarrays to investigate this mechanism.
The main results of this project are as follows:
1. Primary vascular smooth muscle cells were isolated from aortic arteries in female SD rats. Exposure cells to different concentration of 178-estradiol (10~(-9)-10~(-5)M), we found that 178-estradiol increased the SIRT1 protein expression, which was dosage-dependent. Antagonists of ERa and ERβblocked the increasing effects induced by 176-estradiol. We further used agonists of ERa and ERβto stimulated cultured cells. Results shown that agonist of ERa enhanced SIRT1 protein expression but agonist of ERβhad no this effect.
2. We used ovary ectomized rats to study effects of 17B-estradiol on SIRT1. Three groups rats in this experiment including Sham group, ovary ectomized rats and ovary ectomized rats with exogenous 17β-estradiol treatment. All rats were kept for 4 months. Then we isolated brains, hearts, aortic arteries, livers, kidney and skeletal muscles, which were quickly put in liquid nitrogen. We detected SIRT1 in these tissues and found that protein expression of SIRT1 decreased in ovary ectomized rats in comparison with Sham group. Exogenous 17B-estradiol treatment reversed the decreased SIRT1 protein expression.
3. We further used 4 groups in this branch experiments. (1) Sham group; (2) Sham group+CR; (3) ovary ectomized rats; (4) ovary ectomized rats+CR. Totally insulin levels in serum decreased and SIRT1 protein in tissues increased in CR groups. No differences of serum estradiol were found between Sham group and Sham group+CR group. The serum estradiol and progesterone levels significantly increased in ovary ectomized rats+CR compared with ovary ectomized rats. The protein expression of SIRT1 and ERa significantly increased in CR groups.
4. Exposure cultured VSMC to serum from Sham rats and ovary ectomized rats for 48h. We found that SIRT1 protein decreased in cells stimulated by serum from ovary ectomized rats in comparison with Sham rats. We further used rat genome microarrays to identify different gene expression in cells stimulated different serum from Sham rats and ovary ectomized rats for 48h. Our data indicated that 400 genes changed between two groups including metabolic enzymes, stress-related proteins, signal transduction proteins, calcium and potassium ion channels and apoptotic related genes.
The cardioprotective effects of sodium tanshinoneⅡA sulfonate against ischemia-induced injury in rat hearts
Sodium tanshinoneⅡA sulfonate (STS) is a water soluble derivative of tanshinoneⅡA, a well-known Chinese medicine for treating cardiovascular disorders. Cardiomyocyte apoptosis plays a major role in the development of cardiovascular diseases. The present study was designed to investigate the effects of STS on cardiomyocyte apoptosis induced both by in vivo acute myocardial infarction (MI) in adult rats and by in vitro H_2O_2-treated neonatal rat ventricular myocytes. In MI rats, STS significantly reduced the infarct sizes, the blood lactate dehydrogenase (LDH) level and the number of apoptotic cardiomyocytes in the infarcted hearts. In the in vitro study, STS reversed the decreased effect of cell viability induced by H_2O_2. In addition, STS also markedly inhibited H_2O_2-induced cardiomyocyte apoptosis. C-Jun N-terminal kinases/stress-activated protein kinases (JNKs/SAPKs) and p38 MAPK are classic oxidative stress-activated protein kinases. Our further mechanistic study revealed that increased JNK phosphorylation stimulated by H_2O_2 was abolished by STS treatment. In conclusion, inhibition of JNK activation plays a significant role in cardioprotective effects of STS.
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