Induction of Manganese Superoxide Dismutase by Nuclear Translocation and Activation of SIRT1 Promotes Cell Survival in Chronic Heart Failure

Abstract

Oxidative stress plays a pivotal role in chronic heart failure. SIRT1, an NAD ؉ -dependent histone/protein deacetylase, promotes cell survival under oxidative stress when it is expressed in the nucleus. However, adult cardiomyocytes predominantly express SIRT1 in the cytoplasm, and its function has not been elucidated. The purpose of this study was to investigate the functional role of SIRT1 in the heart and the potential use of SIRT1 in therapy for heart failure. We investigated the subcellular localization of SIRT1 in cardiomyocytes and its impact on cell survival. SIRT1 accumulated in the nucleus of cardiomyocytes in the failing hearts of TO-2 hamsters, postmyocardial infarction rats, and a dilated cardiomyopathy patient but not in control healthy hearts. Nuclear but not cytoplasmic SIRT1-induced manganese superoxide dismutase (Mn-SOD), which was further enhanced by resveratrol, and increased the resistance of C2C12 myoblasts to oxidative stress. Resveratrol's enhancement of Mn-SOD levels depended on the level of nuclear SIRT1, and it suppressed the cell death induced by antimycin A or angiotensin II. The cell-protective effects of nuclear SIRT1 or resveratrol were canceled by the Mn-SOD small interfering RNA or SIRT1 small interfering RNA. The oral administration of resveratrol to TO-2 hamsters increased Mn-SOD levels in cardiomyocytes, suppressed fibrosis, preserved cardiac function, and significantly improved survival. Thus, Mn-SOD induced by resveratrol via nuclear SIRT1 reduced oxidative stress and participated in cardiomyocyte protection. SIRT1 activators such as resveratrol could be novel therapeutic tools for the treatment of chronic heart failure.Heart failure arises as a consequence of various heart diseases, including myocardial infarction, hypertension, and idiopathic dilated cardiomyopathy (DCM).2 The death of cardiomyocytes and the consequent maladaptive changes in the remaining myocytes and extracellular matrix induce the clinical manifestation of heart failure (1). Over the past 20 years, the arsenal of treatments available for heart failure has increased considerably, with the introduction of ␤ blockers, angiotensin-converting enzyme inhibitors, angiotensin II type 1 receptor blockers, aldosterone antagonists, and nonpharmacological therapies including cardiac resynchronization therapy (2). However, even with the very best current therapy, the annual mortality rate among patients with heart failure is still ϳ10% (3).The mitochondrial electron transport chain is the main source of reactive oxygen species (ROS) in most cells (4). Hearts consume large amounts of O 2 and yield high levels of ROS (5). Various factors, including angiotensin II and tumor necrosis factor-␣, also induce ROS formation, leading to cardiomyocyte death and heart failure (5). Superoxide dismutase (SOD) has a pivotal role in the detoxification of ROS. SOD catalyzes the dismutation of superoxide into oxygen and hydrogen peroxide, which in turn is reduced to water by catalase and glutathione peroxidase (5). Three isoforms of ...

Recent Advances in the Study on Resveratrol

“…91) Tanno et al reported that manganese superoxide dismutase (Mn-SOD) was induced by 100 μM resveratrol via nuclear translocation and activation of SIRT1 in mouse myoblast C2C12 cells, and that the oral administration of resveratrol (0.4% in diet for 35 weeks) to TO-2 hamsters increased cardiomyocyte Mn-SOD levels, suppressed fibrosis, preserved cardiac function, and significantly improved survival. 92) These results are consistent with our finding that hepatic expression of SIRT1 and Mn-SOD genes was induced by 0.02% resveratrol in the diet for 4 weeks in wild-type mice, but not in PPARα knockout mice (manuscript in preparation). However, 50 μM resveratrol promoted fat mobilization in white adipocytes by repressing PPARγ in 3T3-L1 cells, 93) which is inconsistent with our finding that 5 μM resveratrol activates PPARα, β/δ, and γ in BAECs.…”

Resveratrol Improves Cardiomyopathy in Dystrophin-deficient Mice through SIRT1 Protein-mediated Modulation of p300 Protein*

“…We have shown that SIRT1 is a nucleocytoplasmic shuttling protein (12,13). Furthermore, we found that resveratrol increases superoxide dismutase 2, inhibits cardiomyocyte death, and prolongs the life span in TO-2 cardiomyopathic hamsters (14). We also recently reported that resveratrol reduces oxidative stress and ameliorates the skeletal muscle pathology in mdx mice (15).…”

“…1, F and G) in mdx mice. Previously, we showed that resveratrol represses skeletal muscle fibrosis in mdx mice (15) and cardiac fibrosis in cardiomyopathic TO2 hamsters (14). Down-regulation of ␣-smooth muscle actin expression in mdx hearts treated with resveratrol ( Fig.…”

Hypoxia Increases Sirtuin 1 Expression in a Hypoxia-inducible Factor-dependent Manner

“…Studies of Sirt1 activation to date have primarily focused on post-translational mechanisms of regulation. These mechanisms include changes in pyridine nucleotide levels or ratios that affect Sirt1 enzymatic activity, Sirt1 phosphorylation or other kinase-induced effects (35)(36)(37)(38)(39)(40), or Sirt1 subcellular localization (41)(42)(43)(44). Changes in pyridine nucleotide levels or ratios are perhaps the best studied mechanism for regulating Sirt1 function (45).…”