Novel Role of Silent Information Regulator 1 in Myocardial Ischemia

Abstract

T he incidence of cardiovascular diseases is increasing at an alarming rate throughout the world. According to the World Health Report 2010, cardiovascular disease accounts for 17.1 million global deaths per year, or 29% of total deaths worldwide. It is predicted that this number will increase to 23.6 million by 2030. Myocardial ischemia, which is reported to induce irreversible damage to the myocardium, causes a number of cardiovascular diseases, such as myocardial infarction, myocardial hypertrophy, atherosclerosis, and heart failure. Medical treatment that effectively prevents ischemic injury would alleviate the consequent development of cardiac remodeling and failure. Previous studies have indicated that ischemic preconditioning (IPC), caloric restriction, resveratrol preconditioning, and some related factors can prevent ischemic injury to the heart and are cardioprotective.1 The underlying mechanisms of these interventions appear to be controlled by a nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase called silent information regulator 1 (SIRT1).SIRT1 is a member of the class III group of histone deacetylases, collectively called sirtuins. 2 The mammalian sirtuin family consists of 7 members, designated SIRT1 through SIRT7, which are characterized by a conserved 275-amino-acid catalytic core and unique additional N-terminal and C-terminal sequences of variable length.3 Previous studies have shown that SIRT1 can deacetylate many transcription factors, including forkhead box O (FOXO) transcription factors, p53, nuclear factor-κB (NF-κB), liver X receptor, peroxisome proliferator-activated receptor γ, and brain and muscle Arnt-like protein 1, and nuclear coactivators, as well, including peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), cAMP-responsive element-binding protein-regulated transcription coactivator 2, and period homolog 2.4,5 SIRT1 also deacetylates serine/threonine kinase 11, endothelial nitric oxide synthase (eNOS), and histones H1, H3, and H4.2 It has been reported that SIRT1 performs a wide variety of functions in a variety of biological systems, including obesity-associated metabolic diseases, cancer, aging, cellular senescence, cardiac aging and stress, prion-mediated neurodegeneration, inflammation, and placental cell survival. 5 Most importantly, SIRT1 is involved in cardioprotection.Several studies suggest that SIRT1 plays a role in myocardial ischemia. Pillai and colleagues 6 found that SIRT1 was involved in the effect of fructose feeding on myosin heavy chain (MHC) gene expression and cardiac protection. Additionally, the localization of SIRT1 has been reported to change during cardiac development and under stress conditions. 7 Moreover, Sciarretta and colleagues 8 have reported that SIRT1 plays a role in the cardiac autophagy signaling pathway. In these mechanisms, SIRT1 is controlled by several upstream molecules, such as fructose, Longevinex, nicotinamide phosphoribosyltransferase (Nampt), and microRNA (MIR)-199a. Meanwhile, SIRT1 regulates many...

Upregulated sirtuin 1 by miRNA-34a is required for smooth muscle cell differentiation from pluripotent stem cells

“…SirT1 has been reported to be involved in a variety of cellular functions. 35 Recent data also suggests that SirT1 is a critical mediator in regulation of various development genes during stem cell differentiation 36 and has an important role in various cellular differentiations, including endothelial progenitor cells, 37 hematopoietic cells 38 and osteoblasts. 39 Traditionally, SirT1 has mainly been linked to gene repression; 40 however, accumulating evidence also strongly suggests that SirT1 can act both positively and negatively to control gene expression by recruiting a different set of coactivators and corepressors 41 or via a transcriptional mechanism.…”

Sirtuins, aging, and cardiovascular risks

“…Recent biophysical data indicate that resveratrol interacts with and modulates SIRT1 activity via an allosteric mechanism (Cencioni et al 2015;Hubbard et al 2013;Sinclair and Guarente 2014); these findings interestingly indicate that micromolar levels of resveratrol are sufficient to exert vasculoprotective effects through SIRT1 action (Csiszar et al 2009;Della-Morte et al 2009;Pacholec et al 2010;Ungvari et al 2007;Yang et al 2013). However, some data have suggested that resveratrol seems more likely act through a complex indirect mechanism dependent on the inhibition of phosphodiesterases (PDE) paralleled by AMPK activation (Beher et al 2009;Cencioni et al 2015;Park et al 2012;Yang et al 2013). Furthermore, resveratrol has been further shown to protect coronary endothelial cells against oxidative stress: in fact, it may stimulate in a dose-dependent manner SIRT1 deacetylase activity by increasing its binding affinity to both the acetylated substrate and NAD + (Howitz et al 2003).…”

“…SIRT1 has been confirmed also as a key factor in myocardial hypertrophy; low to moderate SIRT1 heart expression (2.5-to 7.5-fold over endogenous levels) was found to be protective against age-dependent cardiac hypertrophy, apoptosis, and consequent left ventricular dysfunction, whereas SIRT1 overexpression (12.5-fold) induced dilatation, hypertrophy, and cardiac failure (Alcendor et al 2007;Ma et al 2010;Yang et al 2013). SIRT1 also provides protection against apoptosis playing an essential role in mediating the survival of cardiac myocytes under stress in vitro (Alcendor et al 2004;Alcendor et al 2007;Wang et al 2007).…”

“…Notably, SIRT1 activates several members of the FOXO family of transcription factors which promote the expression of stress response genes including antioxidant enzymes (Merksamer et al 2013;Motta et al 2004). Sundaresan et al (2011) demonstrated that whole-body SIRT1 knockout mice have smaller hearts with respect to their wild-type littermates and resist to the development of cardiac hypertrophy related to aging, suggesting that SIRT1 mediates compensated myocardial hypertrophy during ischemia/reperfusion insult (Sunderasan et al 2011;Yang et al 2013). In contrast, cardiomyocyte-specific SIRT1 knockout mice do not show any cardiac abnormalities; however, they are more susceptible to ischemic injury (Pillai et al 2014).…”

“…Resveratrol, a polyphenolic antioxidant found in red wine, activating SIRT1 (Villalba and Alcain 2012;Wallerath et al 2002) prevents oxidative stress and coronary VSMC proliferation inhibiting extracellular signal regulated kinase (ERK) activation (Chong et al 2012;El-Mowafy et al 2008). Recent biophysical data indicate that resveratrol interacts with and modulates SIRT1 activity via an allosteric mechanism (Cencioni et al 2015;Hubbard et al 2013;Sinclair and Guarente 2014); these findings interestingly indicate that micromolar levels of resveratrol are sufficient to exert vasculoprotective effects through SIRT1 action (Csiszar et al 2009;Della-Morte et al 2009;Pacholec et al 2010;Ungvari et al 2007;Yang et al 2013). However, some data have suggested that resveratrol seems more likely act through a complex indirect mechanism dependent on the inhibition of phosphodiesterases (PDE) paralleled by AMPK activation (Beher et al 2009;Cencioni et al 2015;Park et al 2012;Yang et al 2013).…”