SIRT1 suppresses cardiomyocyte apoptosis in diabetic cardiomyopathy: An insight into endoplasmic reticulum stress response mechanism

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; 50 mg/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) (400 mu g/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 (10 mu M) restored SIRT1 levels in cardiomyocytes and markedly reduced ER stress-mediated apoptosis. Conclusion: SIRT1 may attenuate ER stress-induced cardiomyocyte apoptosis via PERK/eIF2 alpha, ATF6/CHOP, and IRE1 alpha/JNK-mediated pathways. This study may provide insights into a novel underlying mechanism and a strategy for treating diabetic cardiomyopathy. (C) 2015 Elsevier Ireland Ltd. All rights reserved.