Rong Guo1, Weijing Liu2, Baoxin Liu2, Buchun Zhang3, Weiming Li2, Yawei Xu4. 1. Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, PR China; Wadsworth Center, New York State Department of Health, Albany, NY 12201, USA. Electronic address: doctorguorong@aliyun.com. 2. Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, PR China. 3. Department of Cardiology, the Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu 221002, PR China. 4. Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, PR China. Electronic address: xuyawei1960@yahoo.com.
Abstract
BACKGROUND: Endoplasmic reticulum (ER) stress-dependent apoptosis had been shown to occur in the hearts of people with diabetes, although the exact mechanisms are unclear. Sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide NAD(+)-dependent deacetylase, is known to play a role in diabetes-related complications as well as ER-stress. Therefore, we investigated the relationship between Sirtuin 1 (SIRT1) and ER stress-induced apoptosis in H9C2 cardiomyocyte. METHODS: Diabetic rats were established by a single intraperitoneal injection of streptozotocin (STZ; 50mg/kg) with high-fat diet. For in vitro analysis, rat derived H9C2 cardiomyocytes were cultured. Cardiac function was assessed by Doppler, and SIRT1 as well as ER stress related protein expressions were measured by immunohistochemistry and western blotting. Cultured cells were exposed to advanced glycation end products (AGEs) (400μg/mL) for inducing ER stress and apoptosis. Cell apoptosis were detected by flow cytometry. RESULTS: In vivo, ER stress was enhanced in the cardiomyocytes of diabetic rats without any treatments. A SIRT1 activator, resveratrol, could significantly restore cardiac function, reduce cardiomyocyte apoptosis, and ameliorate ER stress. In vitro, we showed that apoptosis and ER stress increased after AGE stimulation when SIRT1 expression was downregulated by short interfering RNA (siRNA) (p<0.05). However, resveratrol (10μM) restored SIRT1 levels in cardiomyocytes and markedly reduced ER stress-mediated apoptosis. CONCLUSION: SIRT1 may attenuate ER stress-induced cardiomyocyte apoptosis via PERK/eIF2α, ATF6/CHOP, and IRE1α/JNK-mediated pathways. This study may provide insights into a novel underlying mechanism and a strategy for treating diabetic cardiomyopathy.
BACKGROUND: Endoplasmic reticulum (ER) stress-dependent apoptosis had been shown to occur in the hearts of people with diabetes, although the exact mechanisms are unclear. Sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide NAD(+)-dependent deacetylase, is known to play a role in diabetes-related complications as well as ER-stress. Therefore, we investigated the relationship between Sirtuin 1 (SIRT1) and ER stress-induced apoptosis in H9C2 cardiomyocyte. METHODS:Diabeticrats were established by a single intraperitoneal injection of streptozotocin (STZ; 50mg/kg) with high-fat diet. For in vitro analysis, rat derived H9C2 cardiomyocytes were cultured. Cardiac function was assessed by Doppler, and SIRT1 as well as ER stress related protein expressions were measured by immunohistochemistry and western blotting. Cultured cells were exposed to advanced glycation end products (AGEs) (400μg/mL) for inducing ER stress and apoptosis. Cell apoptosis were detected by flow cytometry. RESULTS: In vivo, ER stress was enhanced in the cardiomyocytes of diabeticrats without any treatments. A SIRT1 activator, resveratrol, could significantly restore cardiac function, reduce cardiomyocyte apoptosis, and ameliorate ER stress. In vitro, we showed that apoptosis and ER stress increased after AGE stimulation when SIRT1 expression was downregulated by short interfering RNA (siRNA) (p<0.05). However, resveratrol (10μM) restored SIRT1 levels in cardiomyocytes and markedly reduced ER stress-mediated apoptosis. CONCLUSION:SIRT1 may attenuate ER stress-induced cardiomyocyte apoptosis via PERK/eIF2α, ATF6/CHOP, and IRE1α/JNK-mediated pathways. This study may provide insights into a novel underlying mechanism and a strategy for treating diabetic cardiomyopathy.
Authors: Man Liu; Guangbin Shi; Anyu Zhou; Cassady E Rupert; Kareen L K Coulombe; Samuel C Dudley Journal: J Mol Cell Cardiol Date: 2018-02-21 Impact factor: 5.000
Authors: Man Liu; Hong Liu; Preethy Parthiban; Gyeoung-Jin Kang; Guangbin Shi; Feng Feng; Anyu Zhou; Lianzhi Gu; Courtney Karnopp; Elena G Tolkacheva; Samuel C Dudley Journal: J Clin Invest Date: 2021-09-15 Impact factor: 14.808