Jie Zhang1,2, Linlin Yao3,4, Shaohua Li3,4, Misbahul Ferdous5, Peng Zhao3,4. 1. Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University Jinan 250012, Shandong, China. 2. Department of Clinical Nutrition, Shandong Provincial Hospital Affiliated to Shandong First Medical University Jinan 250021, Shandong, China. 3. Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University Jinan 250021, Shandong, China. 4. Department of Cardiology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University Jinan 250021, Shandong, China. 5. Department of Cardiology, Fuwai Hospital Beijing 100037, China.
Abstract
OBJECTIVES: Sestrin2 is an essential regulator of the cellular adaptive response against various stresses. The endoplasmic reticulum (ER) is critical in maintaining normal cardiac function by controlling intracellular Ca2+ accumulation, as well as protein folding and processing. Autophagy contributes to stress-associated heart dysfunction. AMP-activated protein kinase (AMPK) is important in energy homeostasis in cardiomyocytes. However, the function of Sestrin2 (Sesn2) in ER stress-induced autophagy that induces myocardial dysfunction has not been clarified. In this study, mice and cardiac tissues were treated with tunicamycin (TN), an inducer of ER stress. We then explored the roles of Sesn2 and the AMPK pathway associated with autophagy in ER stress-induced myocardial dysfunction in mice. METHODS: Echocardiography, contractile function analysis, intracellular Ca2+ status, and immunoblot analysis of AMPK pathway were performed, ER stress and autophagy markers were examined. RESULTS: The study revealed that ER stress caused significant heart dysfunction and cardiotoxicity in the mouse heart and cardiomyocytes. Biochemical analysis indicated enhanced cardiac autophagy mediated by ER stress and AMPK/mTOR activation. Sesn2 knockout exacerbated ER stress-related myocardial dysfunction due to the failed response of cardiac autophagy and AMPK/mTOR pathway activation. Further, pharmacological inhibition of AMPK or autophagy worsened TN-induced cardiac dysfunction. CONCLUSION: Taken together, loss of the Sesn2 protein exacerbates ER stress-induced cardiac dysfunction through the AMPK/mTOR signaling cascade and loss of autophagy response. AJTR
OBJECTIVES: Sestrin2 is an essential regulator of the cellular adaptive response against various stresses. The endoplasmic reticulum (ER) is critical in maintaining normal cardiac function by controlling intracellular Ca2+ accumulation, as well as protein folding and processing. Autophagy contributes to stress-associated heart dysfunction. AMP-activated protein kinase (AMPK) is important in energy homeostasis in cardiomyocytes. However, the function of Sestrin2 (Sesn2) in ER stress-induced autophagy that induces myocardial dysfunction has not been clarified. In this study, mice and cardiac tissues were treated with tunicamycin (TN), an inducer of ER stress. We then explored the roles of Sesn2 and the AMPK pathway associated with autophagy in ER stress-induced myocardial dysfunction in mice. METHODS: Echocardiography, contractile function analysis, intracellular Ca2+ status, and immunoblot analysis of AMPK pathway were performed, ER stress and autophagy markers were examined. RESULTS: The study revealed that ER stress caused significant heart dysfunction and cardiotoxicity in the mouse heart and cardiomyocytes. Biochemical analysis indicated enhanced cardiac autophagy mediated by ER stress and AMPK/mTOR activation. Sesn2 knockout exacerbated ER stress-related myocardial dysfunction due to the failed response of cardiac autophagy and AMPK/mTOR pathway activation. Further, pharmacological inhibition of AMPK or autophagy worsened TN-induced cardiac dysfunction. CONCLUSION: Taken together, loss of the Sesn2 protein exacerbates ER stress-induced cardiac dysfunction through the AMPK/mTOR signaling cascade and loss of autophagy response. AJTR
Authors: Alex Morrison; Li Chen; Jinli Wang; Ming Zhang; Hui Yang; Yina Ma; Andrei Budanov; Jun Hee Lee; Michael Karin; Ji Li Journal: FASEB J Date: 2014-11-03 Impact factor: 5.191