The Mechanism Of Sanshen Weixin Capsula Alleviating Heart Failure Through Endoplasmic Reticulum Stress Pathway

Acute myocardial ischemia and ischemia-reperfusion injury result in thenecrosis and apoptosis of cardiomyocyes. Cardiomyocyte death plays asignificant role in the occurrence and development of myocardial remodelingand heart failure. Endoplasmic reticulum (ER) stress and Autophagy relatedprotein and Ubiquitin proteasome system and Akt signaling pathways involvedin apoptosis process of cardiomyocytes.Objective:It was detected that myocardial structure and the changes of cardiac function,and the expression of ER stress, Autophagy and Ubiquitin proteasome systemrelated signal pathway molecules, and Akt in rat model of heart failure, the aimwas to study the molecular mechanism in the process of development of heartfailure, and to increase understanding the effect and its mechanisms ofSanshen Weixin Capsula against heart failure.Method:The experimental myocardial infarction models in rats established by ligation ofleft anterior descending artery (LAD).The rats are randomly divided into threegroups: Sham, heart failure (HF) group and Sanshen group. After three days ofoperation, rats in the Sanshen group were treated with0.8g/kg Sanshen WexinCapsula for4weeks. And the following experiments were performed:1. The echocardiography and hemodynamic parameters obtained wereselected to evaluate the cardiac function in rats.2. The HE staining and Masson staining were performed to observe themorphological changes and fibrosis of cardiac muscle.3. it was detected that the expression of ER stress related proteins, PERK,p-PERK, eIF2alpha, p-eIF2alpha, ATF-4, CHOP, that of autophagy relatedproteins, Beclin1, p62, LC–3, that of ubiquitin proteasome proteins, Ub,26sproteasome; the expression of apoptosis related proteins, Bim, Bcl-2, Bax,Cytochrome C, Caspase-3, that of Akt and p-Akt by Western Blot.4. It was also detected the expression of p-PERK, CHOP, Ub,26s proteasome, p62, Cleaved Caspase-3and p-Akt proteins by immunohistochemical method.Results:1. Compared with Sham group, it was showed that FS, EF, LVIs, LVPWs, LVSPand±dp/dtmax decrease, the LVIDd, LVIDs and LVEDP increase (p <0.05),and no change in IVSd, LVPWd and LVVd in HF group (p>0.05). Whencompared with HF group, it was showed that the increased FS, EF, LVIs,LVPWs, LVSP and±dp/dtmax, the decreased LVIDd, LVIDs, LVVs and LVEDPin Sanshen group (p <0.05).2. Compared with the Sham group, the section shows the large central area ofcoagulative necrosis of the myocardial fibres, most are smudgy in appearancewith loss of cross-striations, a few karyolytic nuclei are present in rats of HFgroup. It also shows the enhanced collagen deposition in the interstitial space.Compared with HF group, myocardial structure restores, and fibrosis degree isdecreasing in rats of Sanshen group.3. Compared with the Sham group, the myocardium of HF group shows theincreased expression of Bim, Bax, Cytochrome C and cleaved-Caspase-3proteins, the decreasing expression of Bcl-2protein, and the ratio of Bcl-2/Baxalso decreases (p <0.05). Compared with HF group, it shows the decreasedexpression of Bim, Bax, Cytochrome C and cleaved-Caspase-3proteins, theincreasing expression of Bcl-2protein in Sanshen group, and the ratio ofBcl-2/Bax increases (p <0.05).4. Compared with the Sham group, it shows the increased expression ofp-PERK, p-eIF2α, ATF-4and CHOP proteins in HF group (p <0.05).Compared with HF group, it shows the decreased expression of p-PERK,p-eIF2α, ATF-4and CHOP proteins in Sanshen group (p <0.05).5. Compared with the Sham group, it shows the increased expression of Ubprotein (p <0.05), and no change of26s proteasome protein in HF group (p>0.05). Compared with HF group, it shows the decreased expression of Ubprotein, and the increasing expression of26s proteasome protein in Sanshengroup (p <0.05).6. Compared with the Sham group, it shows the increased expression ofBeclin-1, p62and LC-3proteins in HF group (p <0.05). Compared with HFgroup, it shows decreased expression of Beclin-1, p62and LC-3proteins inSanshen group (p <0.05). 7. Compared with the Sham group, it shows the decreased expression of p-Aktprotein in HF group (p <0.05). Compared with HF group, it shows theincreased expression of p-Akt protein in Sanshen group (p <0.05).Conclusion:1. Sanshen Weixin Capsula improves myocardial systolic and diastolicfunction.2. Sanshen Weixin Capsula inhibits cardiomyocytes apoptosis and myocardialfibrosis.3. Sanshen Weixin Capsula decreases the level of endoplasmic reticulumstress and autophagy, and enhances the activities of ubiquitin proteasomesystem and Akt, and alleviates myocardial infarction.