Progressive Reduction in Myocyte Autophagy After Myocardial Infarction in Rabbits: Association with Oxidative Stress and Left Ventricular Remodeling

Cellular Physiology and Biochemistry

Jia-Pu Wang¹  Ke Wang¹  Bao Li¹  Rui-Fang Chi¹  Fu-Zhong Qin¹  Xiao-Li Zhang²  Yue-An Zhang²  Xue-Bin Han²  Yu-Ming Kang³  Bian-Ai Fan⁴ 

[1] a,b,c,d;b,c,d;e;f

关键词: Myocyte autophagy;    Oxidative stress;    Myocardial infarction;    Left ventricular remodeling;   

DOI  :  10.1159/000486167

学科分类：分子生物学，细胞生物学和基因

来源: S Karger AG

【 摘 要 】

Background/Aims The alterations in myocyte autophagy after myocardial infarction (MI) and the underlying mechanisms have not been fully understood. In this study, we investigated the temporal changes of myocyte autophagy in the remote non-infarcted myocardium in rabbits after MI and the relationships between alterations of myocyte autophagy and left ventricular (LV) remodeling and myocardial oxidative stress. Methods Rabbits were assigned to MI or sham operation. Rabbits with MI or sham were randomly assigned to receive chloroquine, an autophagy inhibitor, antioxidant vitamins C and E or placebo for 4 weeks. H9C2 cardiomyocytes were subjected to hypoxia or hydrogen peroxide (H₂O₂) treatment. Results MI rabbits exhibited progressive increases of LV end-diastolic dimension (EDD), and decreases of LV fractional shortening (FS) and dP/dt over 8 weeks. Myocyte autophagy assessed by the scores of LC3 and Beclin1 expression was progressively decreased at 1, 4 and 8 weeks after MI. The ratio of LC3 II/I and Beclin1 and Atg5 proteins were also decreased at 4 weeks after MI. There was a negative correlation between autophagy and LV EDD and a positive correlation between autophagy and LV FS and dP/dt. The autophagy inhibitor chloroquine worsened LV remodeling after MI. Decreased myocyte autophagy was associated with increased myocardial 4-hydroxynonenal. Antioxidant vitamins C and E prevented the decrease in myocyte autophagy after MI. In cultured H9C2 cardiomyocytes, the LC3 II/I ratio was decreased at 4 and 8 h after exposure to hypoxia, and the change was associated with increased 8-hydroxy-2-deoxyguanosine. A low concentration of H₂O₂ decreased the LC3 II/I ratio. Conclusion Progressive reduction in myocyte autophagy in the remote non-infarcted myocardium was associated with myocardial oxidative stress and LV remodeling after MI. Antioxidants prevented the reduction in myocyte autophagy after MI, suggesting that oxidative stress mediates reduction in myocyte autophagy that contributes to post-MI remodeling.

【 授权许可】

CC BY-NC-ND