阿托伐他汀抑制心梗后心衰大鼠心肌细胞凋亡作用机制的研究
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摘要
心肌细胞凋亡是心梗后心衰时心脏重构的重要方面,抑制心肌细胞凋亡可以减轻心脏重构,改善心功能。心衰时心肌细胞凋亡发生机制复杂,目前尚无统一定论。内质网是分布于除成熟红细胞外所有真核细胞的细胞质中的重要细胞器,内质网内膜环境对于确保蛋白质的正确折叠起重要作用。如果内质网内的稳态环境被打破,将通过相应的信号通路引发细胞内一系列的反应,称为内质网应激(endoplasmic reticulum stress, ERS)。内质网的稳态被打乱后,最终会导致大量错误折叠或未被折叠蛋白质在内质网腔中聚集,激活ERS反应。心衰时RAAS, AngⅡ,炎症因子和氧化应激等均可使内质网内环境发生改变,激活ERS反应,过度和/或持续的ERS反应将激活CHOP、和caspase-12凋亡信号通路,最终引起细胞凋亡,因此抑制ERS反应引起的心肌细胞凋亡可以改善心功能。
阿托伐他汀为3-羟基3-甲基戊二酰辅酶A还原酶抑制剂,通过降低血浆中低密度脂蛋白胆固醇(LDL-C)水平而主要用来治疗冠状动脉粥样硬化性心脏病,然而,越来越多的实验表明他汀在心血管疾病中显示出“多效性”作用,其“多效性”作用是独立于降低血脂水平的,其在心力衰竭方面的有益作用越来越受到关注,但其改善心功能的具体机制尚不清楚,故成为目前研究的热点。最新研究发现普伐他汀可以抑制压力负荷诱导心衰大鼠心肌ERS反应,降低心肌细胞凋亡水平,对心功能有保护作用。然而在心梗后心衰模型中阿托伐他汀是否能够抑制心肌ERS反应及其引起的心肌细胞凋亡目前尚不清楚。因此本实验研究阿托伐他汀对心梗后心衰时心肌细胞凋亡的影响及ERS反应在其中的作用,并研究阿托伐他汀对AngⅡ诱导培养的心肌细胞凋亡的影响,进一步探讨ERS反应在其中的作用,以探讨阿托伐他汀对心梗后心衰时心功能的影响及可能机制,为心衰发病机制的研究及寻找更理想的治疗心衰药物提供理论依据。
方法：
通过结扎雌性大鼠冠状动脉左前降支(LAD)制造心梗后心衰动物模型,4w后模型组随机分模型对照组和阿托伐他汀组,并设假手术组为对照组,模型对照组及假手术组给正常饮食,阿托伐他汀组给正常饮食+阿托伐他汀。再连续给药4w后测以下指标：血流动力学检测LVSP、LVEDP和±dp/dtmax; ELISA法测血浆中BNP水平；HE和Masson染色观察心肌病理形态学；TUNEL染色检测心肌细胞凋亡水平；Bcl-2、Bax和caspase-3蛋白表达水平通过免疫组化法检测,mRNA基因表达水平通过PCR法检测;Western blot检测GRP78, caspase-12和CHOP蛋白表达。
体外行雌性乳鼠心肌细胞培养,以AngⅡ诱导心肌细胞凋亡,并给予外源性阿托伐他汀干预,检测以下指标：Western blot检测Bcl-2, Bax和caspase-3蛋白表达；TUNEL染色和流式细胞仪检测心肌细胞凋亡；Western blot检测GRP78、caspase-12和CHOP蛋白表达。
结果：
与假手术组比较,模型对照组大鼠LVEDP增高,LVSP和±dp/dtmax(mmHg/s)减低,且血浆BNP水平增高；心脏体积明显增大,心脏已不能维持正常几何形状,心室腔明显扩大；心肌细胞排列紊乱,大量纤维组织增生；细胞凋亡水平增加；心肌组织Bax和caspase-3蛋白及mRNA基因表达增加,Bcl-2和Bcl-2/Bax蛋白及mRNA基因表达减低；心肌组织中GRP78, caspase-12和CHOP蛋白表达增加。与模型对照组比较,阿托伐他汀组LVEDP减低,LVSP和±dp/dtmax(mmHg/s)增高,血浆BNP水平下降；心脏基本能维持正常几何形状,心室腔扩张程度减轻；心肌细胞排列较整齐,纤维增生程度减弱；心肌细胞凋亡减低；心肌组织Bax和caspase-3蛋白及mRNA基因表达下降,Bcl-2和Bcl-2/Bax蛋白及mRNA基因表达增加,心肌组织GRP78, caspase-12和CHOP蛋白表达减低。进一步分析发现心肌组织GRP78蛋白表达与心肌细胞凋亡水平呈正相关。
体外心肌细胞培养发现AngⅡ可以诱导心肌细胞凋亡,与Cont组比较,AngⅡ组心肌细胞Bcl-2、Bcl-2/Bax蛋白表达减低,Bax和caspase-3蛋白表达增加；心肌细胞凋亡水平增加；GRP78, caspase-12和CHOP蛋白表达增加。而与AngⅡ组比较,AngⅡ+Ator组心肌细胞Bcl-2、Bcl-2/Bax蛋白升高,Bax和caspase-3蛋白减低,心肌细胞凋亡率下降：GRP78, caspase-12和CHOP蛋白表达减低。进一步分析发现心肌细胞GRP78蛋白表达与心肌细胞凋亡水平呈正相关。
结论：
1.本实验通过结扎冠状动脉LAD成功的制作心梗后心衰模型,血流动力学指标LVEDP升高、LVSP和：±dp/dtmax降低及ELISA法检测血浆BNP水平增高,从而证明心梗后心衰模型建立成功。
2.心梗后心衰时存在心脏重构,表现为心腔明显增大,心肌细胞排列紊乱,心肌纤维增生明显；而阿托伐他汀可以稳定心脏正常结构,使心肌细胞排列整齐,并抑制心肌纤维增生；说明阿托伐他汀可以抑制心梗后心衰大鼠心脏重构。
3.心梗后心衰时心肌细胞凋亡参与心脏重构过程,而阿托伐他汀可以抑制心衰时心肌细胞凋亡。
4.心梗后心衰时及AngⅡ诱导的体外培养的心肌细胞中,ERS反应及其引起的CHOP和caspase-12凋亡信号通路参与心肌细胞凋亡,且ERS反应水平与心肌细胞凋亡水平呈正相关,而阿托伐他汀可以通过抑制ERS反应起到抑制心肌细胞凋亡作用。
5.心梗后心衰时及AngⅡ诱导的体外培养的心肌细胞中,Bcl-2/Bax和caspase-3蛋白表达参与心肌细胞凋亡的调控,上调Bcl-2/Bax,下调caspase-3蛋白表达是阿托伐他汀调控心肌细胞凋亡的重要方面。
Cardiamyocyte apoptosis is the major reason for cardiac remodeling during heart failure after myocardial infarction, therefore inhibiting cardiamyocyte apoptosis can reduce cardiac remodeling and improve heart function. At present, the mechanism of apoptosis in heart failure is complicated and unclear. Endoplasmic reticulum(ER) resides in cytoplasm of all eukaryotic cells except for mature erythrocytes. Its unique luminal environment renders its involvement in protein folding. When the environment in ER is broken, a response known as endoplasmic reticulum stress (ERS) or unfolded protein response (UPR) results.RAAS, Angll, oxidative stress and inflammatory responses in heart failure will change the environment of ER and activate ERS response. Excessive and/or persistent ERS response will activate apoptosis signal pathways by transcriptional induction of CCAAT/ enhancer-binding protein (C/EBP) homologous protein (CHOP/GADD 153), the caspase12-dependent pathway and activation of the c-Jun NH2-terminal kinase (JNK)-dependent pathway. Therefore, inhibiting cardiamyocyte apoptosis by inhibiting ERS response can improve heart function.
Atorvastatin is a hydroxy methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statins), widely used in coronary atherosclerosis heart disease by lowering low-density lipoprotein cholesterol (LDL-C) in plasma. Nevertheless, data from both in vitro and in vivo studies suggest that statins have benefits beyond this, generally attributed to the modification of the lipid profile, called pleiotropic effects. These pleiotropic effects are cholesterol independent as its role in heart failure arouses more attentions. Studies have suggested that statins may improve heart function in ischemic and non-ischemic heart failure and reduce mortality. A study has illustrated that pravastatin can suppress ERS response, cardiamyocyte apoptosis in heart failure induced by hypertension, and improvement of heart function by pravastatin. However it is unclear whether atorvastatin can suppress apoptosis by affecting ERS response in heart failure after MI. Therefore, we study the effects of atorvastatin on cardialmyocyte apoptosis and the role of ERS response in order to investigate the mechanism by which atorvastatin improves heart function after MI.
Methods:
Heart failure in female Wistar rat models were created by ligating left artery descending(LAD). After ligating LAD for 4 weeks, the rat models were grouped into Model control group (normal diets, n=16) and Atorvastatin group (normal diets+Atorvastatin lOmg/kg.day, PO, n= 16).And after another 4 weeks, the following indexes were evaluated by hemodynamic:LV end-diastolic pressure (LVEDP), left ventricular systolic pressure(LVSP) and±dp/dt max(mmHg/s). The level of brain natriuretic peptide (BNP) in plasma were examined by ELISA.We assayed the cardiac pathomorphism by HE and Masson staining.To assess the level of myocardium apoptosis in heart failure after MI, the cardiac tissue sections were labeled with an in situ TUNEL assay. The expressions of Bcl-2、Bax and caspase-3 proteins were examined by immunohistochemical analysis and the levels of Bcl-2、Bax and caspase-3 mRNA gene examined by PCR. By Western blot method, GRP78 proteins, representing ERS response and caspase-12 and CHOP proteins reflecting signal pathway of apoptosis induced by ERS response were evaluated.
We cultured cardiamyocyte in vitro from female rats after 1d. Cardiamyocyte apoptosis were induced by Ang II coculturing and atorvastatin were added. After 24h, we examined the expressions of Bcl-2 protein by Western blot assay. The ratio of apoptosis were examined by TUNEL and flow cytometry (FCM).The expressions of GRP89,caspase-12 and CHOP proteins were examined by Western blot.
Results:
Compared with Sham group, in Model control group LVEDP were increased, LVSP and±dp/dt max(mmHg/s) reduced and the levels of BNP in plasma were elevated.In Model group, cardiac volume increased, cardiac can't maintain normal geometric shape. Fibrosis and scar tissues formed in infracted area. However, cardiac volume was smaller in Atorvastatin group than in Model control group and cardiac can keep normal spherical shape. In Model group, An amount of cardiac tissues existed in infarcted zone, an affluence of fibrosis stowed in cardialmyocyte clearance by HE staining was also observed.But in Atorvastatin group cardiamyocyte were in order and there was an little of fiber proliferation. By Masson staining we found that a plenty of collagen and a little cardialmyocyte existed in cardiac tissues in Model group.In Atorvastatin group the number of cardiamyocyte did not reduce and collagen did not increase significantly. In both Model control and Atorvastatin groups, apoptosis was observed in cardiac by TUNEL staining. The index of cardiac apoptosis revealed a significant increase in TUNEL-positive nuclei in Model control group than in Atorvastatin group. The expressions of Bax and caspase-3 proteins and mRNA genes increased and the expressions of Bcl-2 and Bcl-2/Bax proteins and mRNA gene reduced in Model control group.However, atorvastatin can down-regulate the expressions of Bax and caspase-3 proteins and mRNA genes and up-regulate the expressions of Bcl-2 and Bcl-2/Bax proteins and mRNA genes. By Western blot assay, the expressions of GRP78, caspase-12 and CHOP proteins increased significantly in Model control group, but atorvastatin can down-regulate the expressions of GRP78、caspase-12 and CHOP proteins. Furthermore, we found that the expressions of GRP78 protein is positively correlated with cardiamyocyte apoptosis, which illustrated that atorvastatin may improve heart function by suppressing cardialmyocyte apoptosis induced by ERS response in heart failure after MI.
We succeeded in culturing cardialmyocyte in vitro from rats after boring Id. In AngⅡgroup, the expressions of Bcl-2 and Bcl-2/Bax proteins were low, the expressions of Bax and caspase-3 proteins increased by Western blot; Cardialmyocyte apoptosis ratios were increase by TUNEL staining and FCM; the expressions of GRP78,caspase-12 and CHOP proteins by Western blot were increased; however, the expressions of Bcl-2 and Bcl-2/Bax increased Bax and caspase-3 reduced, apoptosis ratio reduced by TUNEL and FCM, the expressions of GRP78, caspase-12 and CHOP proteins reduced in AngⅡ+Ator group. Furthermore, we found that the expressions of GRP78 protein is positively correlated with cardialmyocyte apoptosis, which illustrated that atorvastatin may inhibit cardialmyocyte apoptosis by surpressing ERS response.
Conclusions:
1. We succeeded making heart failure rat models after myocardial infarction by ligating LAD. By hemodynamic, LVEDP were increased, LVSP and≠dp/dt max(mmHg/s) reduced and the level of BNP in plasma were elevated by ELISA, which suggested that heart failure models were made successfully.
2. Cardiac remodeling occured in heart failure after MI:cardiac volume increased exceptionally, cardiamyocyte were irregular and a lot of fibrosis formed. However, in Atorvastatin group, cardiac can keep normal spherical shape and cardialmyocyte were in order and little fiber proliferated. This suggested that atorvastatin can suppress cardiac remodeling in rat with heart failure after MI.
3. Cardialmyocyte apoptosis contributed to cardiac remodeling in heart failure after MI, however, atorvastatin can suppress cardiamyocyte apoptosis in heart failure.
4. The expressions of GRP78, caspase-12 and CHOP proteins increased in heart failure after MI and cultured cardialmyocyte induced by AngⅡ. However, atorvastatin can down-regulate the expressions of GRP78, CHOP and caspase-12 proteins in heart failure after MI and cultured cardialmyocyte induced by AngⅡ. The expressions of GRP78 proteins is positively correlated with cardiamyocyte apoptosis, which illustrated that atorvastatin may improve heart function by surpressing cardialmyocyte apoptosis induced by ERS response in heart failure after MI.
5. The expressions of Bcl-2/Bax and caspase-3 proteins attributed to the regulation of cardialmyocyte apoptosis in heart failure after MI and cultured cardialmyocyte induced by AngⅡ.U p-regulation Bcl-2/Bax and down-regulation caspase-3 proteins were attributed to atorvastatin inhibiting to cardialmyocyte apoptosis.
阿托伐他汀为3-羟基3-甲基戊二酰辅酶A还原酶抑制剂,通过降低血浆中低密度脂蛋白胆固醇(LDL-C)水平而主要用来治疗冠状动脉粥样硬化性心脏病,然而,越来越多的实验表明他汀在心血管疾病中显示出“多效性”作用,其“多效性”作用是独立于降低血脂水平的,其在心力衰竭方面的有益作用越来越受到关注,但其改善心功能的具体机制尚不清楚,故成为目前研究的热点。最新研究发现普伐他汀可以抑制压力负荷诱导心衰大鼠心肌ERS反应,降低心肌细胞凋亡水平,对心功能有保护作用。然而在心梗后心衰模型中阿托伐他汀是否能够抑制心肌ERS反应及其引起的心肌细胞凋亡目前尚不清楚。因此本实验研究阿托伐他汀对心梗后心衰时心肌细胞凋亡的影响及ERS反应在其中的作用,并研究阿托伐他汀对AngⅡ诱导培养的心肌细胞凋亡的影响,进一步探讨ERS反应在其中的作用,以探讨阿托伐他汀对心梗后心衰时心功能的影响及可能机制,为心衰发病机制的研究及寻找更理想的治疗心衰药物提供理论依据。
方法：
通过结扎雌性大鼠冠状动脉左前降支(LAD)制造心梗后心衰动物模型,4w后模型组随机分模型对照组和阿托伐他汀组,并设假手术组为对照组,模型对照组及假手术组给正常饮食,阿托伐他汀组给正常饮食+阿托伐他汀。再连续给药4w后测以下指标：血流动力学检测LVSP、LVEDP和±dp/dtmax; ELISA法测血浆中BNP水平；HE和Masson染色观察心肌病理形态学；TUNEL染色检测心肌细胞凋亡水平；Bcl-2、Bax和caspase-3蛋白表达水平通过免疫组化法检测,mRNA基因表达水平通过PCR法检测;Western blot检测GRP78, caspase-12和CHOP蛋白表达。
体外行雌性乳鼠心肌细胞培养,以AngⅡ诱导心肌细胞凋亡,并给予外源性阿托伐他汀干预,检测以下指标：Western blot检测Bcl-2, Bax和caspase-3蛋白表达；TUNEL染色和流式细胞仪检测心肌细胞凋亡；Western blot检测GRP78、caspase-12和CHOP蛋白表达。
结果：
与假手术组比较,模型对照组大鼠LVEDP增高,LVSP和±dp/dtmax(mmHg/s)减低,且血浆BNP水平增高；心脏体积明显增大,心脏已不能维持正常几何形状,心室腔明显扩大；心肌细胞排列紊乱,大量纤维组织增生；细胞凋亡水平增加；心肌组织Bax和caspase-3蛋白及mRNA基因表达增加,Bcl-2和Bcl-2/Bax蛋白及mRNA基因表达减低；心肌组织中GRP78, caspase-12和CHOP蛋白表达增加。与模型对照组比较,阿托伐他汀组LVEDP减低,LVSP和±dp/dtmax(mmHg/s)增高,血浆BNP水平下降；心脏基本能维持正常几何形状,心室腔扩张程度减轻；心肌细胞排列较整齐,纤维增生程度减弱；心肌细胞凋亡减低；心肌组织Bax和caspase-3蛋白及mRNA基因表达下降,Bcl-2和Bcl-2/Bax蛋白及mRNA基因表达增加,心肌组织GRP78, caspase-12和CHOP蛋白表达减低。进一步分析发现心肌组织GRP78蛋白表达与心肌细胞凋亡水平呈正相关。
体外心肌细胞培养发现AngⅡ可以诱导心肌细胞凋亡,与Cont组比较,AngⅡ组心肌细胞Bcl-2、Bcl-2/Bax蛋白表达减低,Bax和caspase-3蛋白表达增加；心肌细胞凋亡水平增加；GRP78, caspase-12和CHOP蛋白表达增加。而与AngⅡ组比较,AngⅡ+Ator组心肌细胞Bcl-2、Bcl-2/Bax蛋白升高,Bax和caspase-3蛋白减低,心肌细胞凋亡率下降：GRP78, caspase-12和CHOP蛋白表达减低。进一步分析发现心肌细胞GRP78蛋白表达与心肌细胞凋亡水平呈正相关。
结论：
1.本实验通过结扎冠状动脉LAD成功的制作心梗后心衰模型,血流动力学指标LVEDP升高、LVSP和：±dp/dtmax降低及ELISA法检测血浆BNP水平增高,从而证明心梗后心衰模型建立成功。
2.心梗后心衰时存在心脏重构,表现为心腔明显增大,心肌细胞排列紊乱,心肌纤维增生明显；而阿托伐他汀可以稳定心脏正常结构,使心肌细胞排列整齐,并抑制心肌纤维增生；说明阿托伐他汀可以抑制心梗后心衰大鼠心脏重构。
3.心梗后心衰时心肌细胞凋亡参与心脏重构过程,而阿托伐他汀可以抑制心衰时心肌细胞凋亡。
4.心梗后心衰时及AngⅡ诱导的体外培养的心肌细胞中,ERS反应及其引起的CHOP和caspase-12凋亡信号通路参与心肌细胞凋亡,且ERS反应水平与心肌细胞凋亡水平呈正相关,而阿托伐他汀可以通过抑制ERS反应起到抑制心肌细胞凋亡作用。
5.心梗后心衰时及AngⅡ诱导的体外培养的心肌细胞中,Bcl-2/Bax和caspase-3蛋白表达参与心肌细胞凋亡的调控,上调Bcl-2/Bax,下调caspase-3蛋白表达是阿托伐他汀调控心肌细胞凋亡的重要方面。
Cardiamyocyte apoptosis is the major reason for cardiac remodeling during heart failure after myocardial infarction, therefore inhibiting cardiamyocyte apoptosis can reduce cardiac remodeling and improve heart function. At present, the mechanism of apoptosis in heart failure is complicated and unclear. Endoplasmic reticulum(ER) resides in cytoplasm of all eukaryotic cells except for mature erythrocytes. Its unique luminal environment renders its involvement in protein folding. When the environment in ER is broken, a response known as endoplasmic reticulum stress (ERS) or unfolded protein response (UPR) results.RAAS, Angll, oxidative stress and inflammatory responses in heart failure will change the environment of ER and activate ERS response. Excessive and/or persistent ERS response will activate apoptosis signal pathways by transcriptional induction of CCAAT/ enhancer-binding protein (C/EBP) homologous protein (CHOP/GADD 153), the caspase12-dependent pathway and activation of the c-Jun NH2-terminal kinase (JNK)-dependent pathway. Therefore, inhibiting cardiamyocyte apoptosis by inhibiting ERS response can improve heart function.
Atorvastatin is a hydroxy methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statins), widely used in coronary atherosclerosis heart disease by lowering low-density lipoprotein cholesterol (LDL-C) in plasma. Nevertheless, data from both in vitro and in vivo studies suggest that statins have benefits beyond this, generally attributed to the modification of the lipid profile, called pleiotropic effects. These pleiotropic effects are cholesterol independent as its role in heart failure arouses more attentions. Studies have suggested that statins may improve heart function in ischemic and non-ischemic heart failure and reduce mortality. A study has illustrated that pravastatin can suppress ERS response, cardiamyocyte apoptosis in heart failure induced by hypertension, and improvement of heart function by pravastatin. However it is unclear whether atorvastatin can suppress apoptosis by affecting ERS response in heart failure after MI. Therefore, we study the effects of atorvastatin on cardialmyocyte apoptosis and the role of ERS response in order to investigate the mechanism by which atorvastatin improves heart function after MI.
Methods:
Heart failure in female Wistar rat models were created by ligating left artery descending(LAD). After ligating LAD for 4 weeks, the rat models were grouped into Model control group (normal diets, n=16) and Atorvastatin group (normal diets+Atorvastatin lOmg/kg.day, PO, n= 16).And after another 4 weeks, the following indexes were evaluated by hemodynamic:LV end-diastolic pressure (LVEDP), left ventricular systolic pressure(LVSP) and±dp/dt max(mmHg/s). The level of brain natriuretic peptide (BNP) in plasma were examined by ELISA.We assayed the cardiac pathomorphism by HE and Masson staining.To assess the level of myocardium apoptosis in heart failure after MI, the cardiac tissue sections were labeled with an in situ TUNEL assay. The expressions of Bcl-2、Bax and caspase-3 proteins were examined by immunohistochemical analysis and the levels of Bcl-2、Bax and caspase-3 mRNA gene examined by PCR. By Western blot method, GRP78 proteins, representing ERS response and caspase-12 and CHOP proteins reflecting signal pathway of apoptosis induced by ERS response were evaluated.
We cultured cardiamyocyte in vitro from female rats after 1d. Cardiamyocyte apoptosis were induced by Ang II coculturing and atorvastatin were added. After 24h, we examined the expressions of Bcl-2 protein by Western blot assay. The ratio of apoptosis were examined by TUNEL and flow cytometry (FCM).The expressions of GRP89,caspase-12 and CHOP proteins were examined by Western blot.
Results:
Compared with Sham group, in Model control group LVEDP were increased, LVSP and±dp/dt max(mmHg/s) reduced and the levels of BNP in plasma were elevated.In Model group, cardiac volume increased, cardiac can't maintain normal geometric shape. Fibrosis and scar tissues formed in infracted area. However, cardiac volume was smaller in Atorvastatin group than in Model control group and cardiac can keep normal spherical shape. In Model group, An amount of cardiac tissues existed in infarcted zone, an affluence of fibrosis stowed in cardialmyocyte clearance by HE staining was also observed.But in Atorvastatin group cardiamyocyte were in order and there was an little of fiber proliferation. By Masson staining we found that a plenty of collagen and a little cardialmyocyte existed in cardiac tissues in Model group.In Atorvastatin group the number of cardiamyocyte did not reduce and collagen did not increase significantly. In both Model control and Atorvastatin groups, apoptosis was observed in cardiac by TUNEL staining. The index of cardiac apoptosis revealed a significant increase in TUNEL-positive nuclei in Model control group than in Atorvastatin group. The expressions of Bax and caspase-3 proteins and mRNA genes increased and the expressions of Bcl-2 and Bcl-2/Bax proteins and mRNA gene reduced in Model control group.However, atorvastatin can down-regulate the expressions of Bax and caspase-3 proteins and mRNA genes and up-regulate the expressions of Bcl-2 and Bcl-2/Bax proteins and mRNA genes. By Western blot assay, the expressions of GRP78, caspase-12 and CHOP proteins increased significantly in Model control group, but atorvastatin can down-regulate the expressions of GRP78、caspase-12 and CHOP proteins. Furthermore, we found that the expressions of GRP78 protein is positively correlated with cardiamyocyte apoptosis, which illustrated that atorvastatin may improve heart function by suppressing cardialmyocyte apoptosis induced by ERS response in heart failure after MI.
We succeeded in culturing cardialmyocyte in vitro from rats after boring Id. In AngⅡgroup, the expressions of Bcl-2 and Bcl-2/Bax proteins were low, the expressions of Bax and caspase-3 proteins increased by Western blot; Cardialmyocyte apoptosis ratios were increase by TUNEL staining and FCM; the expressions of GRP78,caspase-12 and CHOP proteins by Western blot were increased; however, the expressions of Bcl-2 and Bcl-2/Bax increased Bax and caspase-3 reduced, apoptosis ratio reduced by TUNEL and FCM, the expressions of GRP78, caspase-12 and CHOP proteins reduced in AngⅡ+Ator group. Furthermore, we found that the expressions of GRP78 protein is positively correlated with cardialmyocyte apoptosis, which illustrated that atorvastatin may inhibit cardialmyocyte apoptosis by surpressing ERS response.
Conclusions:
1. We succeeded making heart failure rat models after myocardial infarction by ligating LAD. By hemodynamic, LVEDP were increased, LVSP and≠dp/dt max(mmHg/s) reduced and the level of BNP in plasma were elevated by ELISA, which suggested that heart failure models were made successfully.
2. Cardiac remodeling occured in heart failure after MI:cardiac volume increased exceptionally, cardiamyocyte were irregular and a lot of fibrosis formed. However, in Atorvastatin group, cardiac can keep normal spherical shape and cardialmyocyte were in order and little fiber proliferated. This suggested that atorvastatin can suppress cardiac remodeling in rat with heart failure after MI.
3. Cardialmyocyte apoptosis contributed to cardiac remodeling in heart failure after MI, however, atorvastatin can suppress cardiamyocyte apoptosis in heart failure.
4. The expressions of GRP78, caspase-12 and CHOP proteins increased in heart failure after MI and cultured cardialmyocyte induced by AngⅡ. However, atorvastatin can down-regulate the expressions of GRP78, CHOP and caspase-12 proteins in heart failure after MI and cultured cardialmyocyte induced by AngⅡ. The expressions of GRP78 proteins is positively correlated with cardiamyocyte apoptosis, which illustrated that atorvastatin may improve heart function by surpressing cardialmyocyte apoptosis induced by ERS response in heart failure after MI.
5. The expressions of Bcl-2/Bax and caspase-3 proteins attributed to the regulation of cardialmyocyte apoptosis in heart failure after MI and cultured cardialmyocyte induced by AngⅡ.U p-regulation Bcl-2/Bax and down-regulation caspase-3 proteins were attributed to atorvastatin inhibiting to cardialmyocyte apoptosis.
引文
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