The Effects Of Endoplasmic Reticulum Stress On Cardiomyocyte Apoptosis After Acute Myocardial Infarction In Rats

It has been suggested that apoptosis may be responsible for a significant amount of cardiomyocyte death during post-infarction cardiac remodeling and heart failure. Recent studies have shown that in addition to the death receptor and mitochondrial death pathways, there also exists the endoplasmic reticulum stress-induced apoptotic pathway. Many disturbances, such as hypoxia, glucose deprivation and drug, which cause accumulation of unfolded/misfolded proteins and aberrant Ca2+ regulation, lead to ER stress, triggering the unfolded protein response (UPR). UPR induces expression of ER chaperones GRP78 and phosophorlation of eukaryotic translation initiation factors 2α(eIF2α)to reduce the accumulation of unfolded protein by inhibiting protein translation, which leads to protection of cells. However, prolonged ER stress with the failure of celular protective mechanisms by UPR will eventually activates the expression of caspase-12 and CHOP/GADD153, two chaperones in ERS apoptosis pathway, and finally results in cell apoptosis.It has been reported that ER stress is involved in many heart diseases such as cardiomyopathy, heart failure and atherosclerosis and so on. However, the exact mechanisms of ER stress in these diseases still remain unclear and fewer publications are found between ERS and AMI.Through the early in vitro experiments,we confirm that hypoxia can induce cardiomyocyte apoptosis by ERS apoptosis pathway. Thus we consider whether myocardial ischemia/hypoxia would also induce myocardial cell apoptosis through ERS pathway in vivo. In this research, we established the model of myocardial infarction and observed how endoplasmic reticulum stress and related signaling pathway works after myocardial infarction. We explore the changing patterns of ERS in cardiomyocyte apoptosis after AMI to reveal the importance of ERS-induced apoptotic pathway in myocardial infarction.Model of myocardial infarction was established by ligation of the left anterior descending branch. The myocardial pathological injury was observed by Haematoxylin-Eosin staining and apoptosis of cardiomyocyte was examined using TUNEL at 1,3,6,12,24h after myocardial infarction. We use immunohistochemical staining and Western blot to detect protein expression of endoplasmic reticulum stress related molecular chaperone GRP78, e IF2α,p-e IF2αand apotosis proteins caspase-12 and GADD153/CHOP at different time points, in order to get the relationship between endoplasmic reticulum stress and myocardial infarction.The results showed that the 24h-operated group had the most lesions. The apoptotic index peaked at 24h (P<0.05). The expression of GRP78 and phosphorylation of e IF2αup to the peak at 6 hours after myocardial infarction (P＜0.05). The expression of caspase-12 and CHOP was maximum in 24h-operated group(P＜0.05). These findings indicate that myocardial infarction can induce UPR. When ER stress conditions persisit, initiation of apoptotic process is promoted. The changing trend of these ER-localized molecular chaperones is at equal pace with cardiomyocyte apoptosis. This suggests that that endoplasmic reticulum stress may play an important role in the course of apoptosis of cardiomyocyte induced by myocardial infarction.