logo logo
Metformin improves cardiac function in mice with heart failure after myocardial infarction by regulating mitochondrial energy metabolism. Sun Dan,Yang Fei Biochemical and biophysical research communications To investigate whether metformin can improve the cardiac function through improving the mitochondrial function in model of heart failure after myocardial infarction. Male C57/BL6 mice aged about 8 weeks were selected and the anterior descending branch was ligatured to establish the heart failure model after myocardial infarction. The cardiac function was evaluated via ultrasound after 3 days to determine the modeling was successful, and the mice were randomly divided into two groups. Saline group (Saline) received the intragastric administration of normal saline for 4 weeks, and metformin group (Met) received the intragastric administration of metformin for 4 weeks. At the same time, Shame group (Sham) was set up. Changes in cardiac function in mice were detected at 4 weeks after operation. Hearts were taken from mice after 4 weeks, and cell apoptosis in myocardial tissue was detected using TUNEL method; fresh mitochondria were taken and changes in oxygen consumption rate (OCR) and respiratory control rate (RCR) of mitochondria in each group were detected using bio-energy metabolism tester, and change in mitochondrial membrane potential (MMP) of myocardial tissue was detected via JC-1 staining; the expressions and changes in Bcl-2, Bax, Sirt3, PGC-1α and acetylated PGC-1α in myocardial tissue were detected by Western blot. RT-PCR was used to detect mRNA levels in Sirt3 in myocardial tissues. Metformin improved the systolic function of heart failure model rats after myocardial infarction and reduced the apoptosis of myocardial cells after myocardial infarction. Myocardial mitochondrial respiratory function and membrane potential were decreased after myocardial infarction, and metformin treatment significantly improved the mitochondrial respiratory function and mitochondrial membrane potential; Metformin up-regulated the expression of Sirt3 and the activity of PGC-1α in myocardial tissue of heart failure after myocardial infarction. Metformin decreases the acetylation level of PGC-1α through up-regulating Sirt3, mitigates the damage to mitochondrial membrane potential of model of heart failure after myocardial infarction and improves the respiratory function of mitochondria, thus improving the cardiac function of mice. 10.1016/j.bbrc.2017.03.036
Doxorubicin Blocks Cardiomyocyte Autophagic Flux by Inhibiting Lysosome Acidification. Li Dan L,Wang Zhao V,Ding Guanqiao,Tan Wei,Luo Xiang,Criollo Alfredo,Xie Min,Jiang Nan,May Herman,Kyrychenko Viktoriia,Schneider Jay W,Gillette Thomas G,Hill Joseph A Circulation BACKGROUND:The clinical use of doxorubicin is limited by cardiotoxicity. Histopathological changes include interstitial myocardial fibrosis and the appearance of vacuolated cardiomyocytes. Whereas dysregulation of autophagy in the myocardium has been implicated in a variety of cardiovascular diseases, the role of autophagy in doxorubicin cardiomyopathy remains poorly defined. METHODS AND RESULTS:Most models of doxorubicin cardiotoxicity involve intraperitoneal injection of high-dose drug, which elicits lethargy, anorexia, weight loss, and peritoneal fibrosis, all of which confound the interpretation of autophagy. Given this, we first established a model that provokes modest and progressive cardiotoxicity without constitutional symptoms, reminiscent of the effects seen in patients. We report that doxorubicin blocks cardiomyocyte autophagic flux in vivo and in cardiomyocytes in culture. This block was accompanied by robust accumulation of undegraded autolysosomes. We go on to localize the site of block as a defect in lysosome acidification. To test the functional relevance of doxorubicin-triggered autolysosome accumulation, we studied animals with diminished autophagic activity resulting from haploinsufficiency for Beclin 1. Beclin 1(+/-) mice exposed to doxorubicin were protected in terms of structural and functional changes within the myocardium. Conversely, animals overexpressing Beclin 1 manifested an amplified cardiotoxic response. CONCLUSIONS:Doxorubicin blocks autophagic flux in cardiomyocytes by impairing lysosome acidification and lysosomal function. Reducing autophagy initiation protects against doxorubicin cardiotoxicity. 10.1161/CIRCULATIONAHA.115.017443
HMGB1 contributes to adriamycin-induced cardiotoxicity via up-regulating autophagy. Luo Peihua,Zhu Yi,Chen Min,Yan Hao,Yang Bo,Yang Xiaochun,He Qiaojun Toxicology letters Adriamycin (ADR) is one of the most widely used and effective anthracycline antitumor agents in the treatment of certain hematological malignancies and solid tumors. However, the severe cardiotoxicity of ADR limits its clinical application. So far, the mechanism of the cardiotoxicity of ADR has not been completely clarified. In our research, cardiomyocyte autophagy and cardiac damage were observed in accompany ADR treatment, and autophagy appeared earlier than cardiac damage. Inhibition of autophagy by silencing ATG7 improved the survival rate of cardiomyocytes treated with ADR. The release of HMGB1 increased after ADR treatment, and silencing HMGB1 could reverse cardiomyocyte damage by attenuating autophagy. In addition, the expression of YAP was decreased, and overexpressing YAP down-regulated HMGB1 and alleviated cardiomyocyte damage. These results indicated that autophagy was the leading cause of ADR-induced cardiotoxicity, and HMGB1 played a vital role in the process of up-regulating autophagy. 10.1016/j.toxlet.2018.04.034