【摘 要】
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An increase in cardiomyocyte apoptosis is the main contributor to the observed high morbid-ity of cardiac disease during aging.Mitochondria play important roles in cardiac apoptosis,and dynamin-related protein 1 (Drp1) is the critical factor that particip
【机 构】
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Department of Physiology and Pathophysiology,School of Basic Medical Sciences,Capital Medical Univer
论文部分内容阅读
An increase in cardiomyocyte apoptosis is the main contributor to the observed high morbid-ity of cardiac disease during aging.Mitochondria play important roles in cardiac apoptosis,and dynamin-related protein 1 (Drp1) is the critical factor that participates in mitochondrial fission and induces mitophagy to maintain mitochondria quality.However,whether Drp1 is involved in the increase of apoptosis in aging heart remains unclear.The purpose of this study was to determine whether Drp1 participates in inducing the apoptosis through regu-lating mitophagy in aging myocardium.To explore the effect of mitophagy and apoptosis in aging heart,we detected the expression of COX Ⅳ and the co-localization of COX Ⅳ and LC3 Ⅱ,which reflect mitophagy,and measured adenosine triphosphate and reactive oxygen species contents,which reflect mitochondrial injury.Cell apoptosis was detected by measur-ing the activity of caspase-3 and the expression of cleaved caspase-3 and further confirmed by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay.The results showed an increase in apoptosis and a decrease in mitophagy in aging cardiomy-ocytes,and apoptosis was ameliorated after the induction of mitophagy by carbonyl cyanide m-chlorophenyl hydrazone (a mitophagy activator) in D-galactose (D-gal)-induced senescence H9c2 cells.To clarify the role of Drp1 in apoptosis,we knocked down Drp1 by transfecting si-Drp1,or overexpressed Drp1 in senescent cells,and then detected mitophagy,mitochondrial injury,and apoptosis.The data showed that downregulated Drp1 induces mitochondrial damage and apoptosis.In addition,to explore the regulatory relationship between Drp1 and phosphatase and tensin homologue (PTEN)-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy,we detected the expressions of PINK1 and Parkin after the overexpression of Drp1 in the D-gal group cells and found that Drp1-mediated mitophagy inhibited the PINK1/Parkin pathway in senescent cells.Our results demonstrated that insufficient Drp1 induces cardiomyocyte apoptosis by inhibiting mitophagy,and Drp1 affects the PINK1/Parkin pathway of mitophagy in the aging heart.
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