Contribution Of Endoplasmic Reticulum Stress To Cardiac Myocyte Apoptosis In Mouse Congestive Heart Failure Derived From Myocardial Infraction

BackgroundHeart failure is the syndrome of the major complication and end-stage of variety serious heart disease. Once patients with heart failure have the typical symptoms, the condition will be exacerbated and mortality similar to patients with cancer. In addition to the pathogenesis of heart failure, such as hemodynamic abnormalities, neuroendocrine activation and ventricular remodeling, the role of apoptosis in heart failure get more attention, apoptosis can reduce the absolute number of myocardial cells, which led to decreased myocardial contractility. Experimental studies and clinical trials all show that intervention of apoptosis is an effective way in the therapy heart failure. In recent years, the study found that the apoptosis mechanism of endoplasmic reticulum stress-mediated apoptosis is a new signaling pathway of apoptosis. Endoplasmic reticulum stress response is a self-protective mechanism, involving a variety of signal response pathway system and regulation of many genes. Endoplasmic reticulum stress can activate the expression of endoplasmic reticulum molecular chaperone, endoplasmic reticulum associated death etc to protect cells against stress, make organ survival by induce the activation of apoptosis. However,the heavy and continued endoplasmic reticulum stress can lead to cell dysfunction and even cell death. In the cardiovascular system, endoplasmic reticulum stress as a common pathway for a variety of stress in the process, and extensive participated in the pathophysiological processes of variety of cardiovascular diseases.There are three pathways of endoplasmic reticulum associated death, including CCAAT / enhancer binding proteinε(CHOP), c-Jun N-terminal kinase (JNK) and caspase-12 pathway. However, the study found that in heart failure model induced by aortic coarctation which enhanced the pressure overload of heart sustained endoplasmic reticulum stress and induced cardiomyocyte apoptosis through CHOP pathway rather than JNK, caspase-12 pathway. In the model of heart failure which induced by Adriamycin, the caspase-12, which located in the sarcoplasmic reticulum, played an important role, and the activation of caspase-12 can induced the apopotosis through endoplasmic reticulum stress independently. All these study implied that JNK, caspase-12 and CHOP three pathway can play diffrent role in the diffrent pathophysiological processes of endoplasmic reticulum associated death.We will make the model of mouse heart failure which is induced by acute myocardial infarction by ligating the left anterior descending coronary,and explore the role of the CHOP, JNK, capase-12 three pathways in the pathophysiological processes of endoplasmic reticulum associated death.Objective1. To explore the contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis in mouse congestive heart failure derived from myocardial infraction.2. To explore the role of the CHOP, JNK, capase-12 three pathways in the pathophysiological processes of mouse congestive heart failure derived from myocardial infraction.Methods1. The mouse heart failure was induced by acute myocardial infarction by ligating the left anterior descending coronary.Thirty-two mice were divided into four groups:sham group, groups in 2, 4, 6 weeks post-operation, respectively. The ventricular dilatation and left ventricular function were assessed by echocardiography.2. The expression of GRP78, CHOP, caspase-12, cleaved caspase-12, JNK, phosphorylated-JNK were assessed by western blot.3. The cardiac myocyte apoptosis were assessed by Terminal Deoxynucleotidyl Transferase Mediated dUTP-Biotin Nick End Labeling(TUNEL).Result1. Cardiac expression of endoplasmic reticulum chaperones GRP78 was significantly increased in the congestive heart failure derived from myocardial infraction. 2. The upregulated expression of CHOP, phosphorylated-JNK and cleaved caspase-12 illuminated that the CHOP-,JNK-,capase-12 dependent pathways for endoplasmic reticulum-initiated apoptosis was activated in failing heart by myocardial infraction.Conclusion1. The congestive heart failure derived from myocardial infraction induced endoplasmic reticulum stress.2. The CHOP, JNK, capase-12 dependent pathways for endoplasmic reticulum-initiated apoptosis was involved in the cell apoptosis in the congestive heart failure derived from myocardial infraction .