Shanjie Wang1, Yanhong Fan1, Xinyu Feng1, Chuang Sun2, Zhaofeng Shi3, Tian Li1, Jianjun Lv1, Zhi Yang1, Zhijing Zhao4, Dongdong Sun5. 1. Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China. 2. Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China. 3. Department of Traditional Chinese Medicine, Xijing Hospital Affiliated to Fourth Military Medical University, Xi'an, China. 4. Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China. Electronic address: zhaozhj@fmmu.edu.cn. 5. Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China. Electronic address: wintersun3@gmail.com.
Abstract
BACKGROUND: Cardiomyocyte autophagy and apoptosis are crucial events underlying the development of cardiac abnormalities and dysfunction after myocardial infarction (MI). A better understanding of the cell signaling pathways involved in cardiac remodeling may support the development of new therapeutic strategies for the treatment of heart failure (HF) after MI. METHODS: A cardiac MI injury model was constructed by ligating the left anterior descending (LAD) coronary artery. Neonatal cardiomyocytes were isolated and cultured to investigate the mechanisms underlying the protective effects of nicorandil on MI-induced injury. RESULTS: Nicorandil reduced cardiac enzyme release, mitigated left ventricular enlargement and cardiac dysfunction after MI, as evaluated by echocardiography and hemodynamic measurements. According to the results of the western blot analysis and immunofluorescence staining, nicorandil enhanced autophagic flux and reduced apoptosis in cardiomyocytes subjected to hypoxic injury. Interestingly, nicorandil increased Mst1 and p-Mst1 levels in cardiomyocytes subjected to MI injury. Mst1 knockout abolished the protective effects of nicorandil on cardiac remodeling and dysfunction after MI. Mst1 knockout also abolished the beneficial effects of nicorandil on cardiac enzyme release and cardiomyocyte autophagy and apoptosis. CONCLUSIONS: Nicorandil alleviates post-MI cardiac dysfunction and remodeling. The mechanisms were associated with enhancing autophagy and inhibiting apoptosis through Mst1 inhibition.
BACKGROUND: Cardiomyocyte autophagy and apoptosis are crucial events underlying the development of cardiac abnormalities and dysfunction after myocardial infarction (MI). A better understanding of the cell signaling pathways involved in cardiac remodeling may support the development of new therapeutic strategies for the treatment of heart failure (HF) after MI. METHODS: A cardiac MI injury model was constructed by ligating the left anterior descending (LAD) coronary artery. Neonatal cardiomyocytes were isolated and cultured to investigate the mechanisms underlying the protective effects of nicorandil on MI-induced injury. RESULTS:Nicorandil reduced cardiac enzyme release, mitigated left ventricular enlargement and cardiac dysfunction after MI, as evaluated by echocardiography and hemodynamic measurements. According to the results of the western blot analysis and immunofluorescence staining, nicorandil enhanced autophagic flux and reduced apoptosis in cardiomyocytes subjected to hypoxic injury. Interestingly, nicorandil increased Mst1 and p-Mst1 levels in cardiomyocytes subjected to MI injury. Mst1 knockout abolished the protective effects of nicorandil on cardiac remodeling and dysfunction after MI. Mst1 knockout also abolished the beneficial effects of nicorandil on cardiac enzyme release and cardiomyocyte autophagy and apoptosis. CONCLUSIONS:Nicorandil alleviates post-MI cardiac dysfunction and remodeling. The mechanisms were associated with enhancing autophagy and inhibiting apoptosis through Mst1 inhibition.
Authors: Rachel T Sullivan; Ngoc T Lam; Margaret Haberman; Margaret J Beatka; Muhammad Z Afzal; Michael W Lawlor; Jennifer L Strande Journal: BMC Cardiovasc Disord Date: 2021-06-15 Impact factor: 2.298