SIRT2 Acts as a Cardioprotective Deacetylase in Pathological Cardiac Hypertrophy

Background: Pathological cardiac hypertrophy induced by stresses such as aging and neurohumoral activation is an independent risk factor for heart failure and is considered a target for the treatment of heart failure. However, the mechanisms underlying pathological cardiac hypertrophy remain largely unknown. We aimed to investigate the roles of SIRT2 in aging-related and angiotensin II (Ang II)–induced pathological cardiac hypertrophy. Methods: Male C57BL/6J wild-type and Sirt2 knockout mice were subjected to the investigation of aging-related cardiac hypertrophy. Cardiac hypertrophy was also induced by Ang II (1.3 mg/kg/d for 4 weeks) in male C57BL/6J Sirt2 knockout mice, cardiac-specific SIRT2 transgenic (SIRT2-Tg) mice, and their respective littermates (8 to ≈12 weeks old). Metformin (200 mg/kg/d) was used to treat wild-type and Sirt2 knockout mice infused with Ang II. Cardiac hypertrophy, fibrosis, and cardiac function were examined in these mice. Results: SIRT2 protein expression levels were downregulated in hypertrophic hearts from mice. Sirt2 knockout markedly exaggerated cardiac hypertrophy and fibrosis and decreased cardiac ejection fraction and fractional shortening in aged (24-month-old) mice and Ang II–infused mice. Conversely, cardiac-specific SIRT2 overexpression protected the hearts against Ang II–induced cardiac hypertrophy and fibrosis and rescued cardiac function. Mechanistically, SIRT2 maintained the activity of AMP-activated protein kinase (AMPK) in aged and Ang II–induced hypertrophic hearts in vivo as well as in cardiomyocytes in vitro. We identified the liver kinase B1 (LKB1), the major upstream kinase of AMPK, as the direct target of SIRT2. SIRT2 bound to LKB1 and deacetylated it at lysine 48, which promoted the phosphorylation of LKB1 and the subsequent activation of LKB1-AMPK signaling. Remarkably, the loss of SIRT2 blunted the response of AMPK to metformin treatment in mice infused with Ang II and repressed the metformin-mediated reduction of cardiac hypertrophy and protection of cardiac function. Conclusions: SIRT2 promotes AMPK activation by deacetylating the kinase LKB1. Loss of SIRT2 reduces AMPK activation, promotes aging-related and Ang II–induced cardiac hypertrophy, and blunts metformin-mediated cardioprotective effects. These findings indicate that SIRT2 will be a potential target for therapeutic interventions in aging- and stress-induced cardiac hypertrophy.

[1]  De-Pei Liu,et al.  Mitochondrial Sirtuins in cardiometabolic diseases. , 2017, Clinical science.

[2]  Matthew J. Crowley,et al.  Clinical Outcomes of Metformin Use in Populations With Chronic Kidney Disease, Congestive Heart Failure, or Chronic Liver Disease , 2017, Annals of Internal Medicine.

[3]  D. Sinclair,et al.  Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds , 2016, Nature Reviews Molecular Cell Biology.

[4]  H. Tse,et al.  Endothelial SIRT1 prevents adverse arterial remodeling by facilitating HERC2-mediated degradation of acetylated LKB1 , 2016, Oncotarget.

[5]  M. Brownlee,et al.  Molecular and Cellular Mechanisms of Cardiovascular Disorders in Diabetes. , 2016, Circulation research.

[6]  J. Sadoshima,et al.  Aging and Autophagy in the Heart. , 2016, Circulation research.

[7]  De-Pei Liu,et al.  SIRT4 accelerates Ang II-induced pathological cardiac hypertrophy by inhibiting manganese superoxide dismutase activity , 2016, European heart journal.

[8]  Johan Auwerx,et al.  Metabolomics-assisted proteomics identifies succinylation and SIRT5 as important regulators of cardiac function , 2016, Proceedings of the National Academy of Sciences.

[9]  R. Chhipa,et al.  Evolving Lessons on the Complex Role of AMPK in Normal Physiology and Cancer. , 2016, Trends in pharmacological sciences.

[10]  C. Cavadas,et al.  Emerging Role of Sirtuin 2 in the Regulation of Mammalian Metabolism. , 2015, Trends in pharmacological sciences.

[11]  J. Auwerx,et al.  Protective effects of sirtuins in cardiovascular diseases: from bench to bedside , 2015, European heart journal.

[12]  Joseph A. Hill,et al.  Inhibition of hypertrophy is a good therapeutic strategy in ventricular pressure overload. , 2015, Circulation.

[13]  E. Braunwald.  The war against heart failure: the Lancet lecture , 2015, The Lancet.

[14]  J. Dyck,et al.  Is AMPK the savior of the failing heart? , 2015, Trends in Endocrinology & Metabolism.

[15]  B. Viollet,et al.  Metformin: from mechanisms of action to therapies. , 2014, Cell metabolism.

[16]  Sung Ho Lee,et al.  Src regulates the activity of SIRT2. , 2014, Biochemical and biophysical research communications.

[17]  B. Kennedy,et al.  Late‐life rapamycin treatment reverses age‐related heart dysfunction , 2013, Aging cell.

[18]  Frank Fischer,et al.  An acetylome peptide microarray reveals specificities and deacetylation substrates for all human sirtuin isoforms , 2013, Nature Communications.

[19]  Torsten Doenst,et al.  Cardiac Metabolism in Heart Failure: Implications Beyond ATP Production , 2013, Circulation research.

[20]  Xinli Hu,et al.  Microtubule Actin Cross-Linking Factor 1 Regulates Cardiomyocyte Microtubule Distribution and Adaptation to Hemodynamic Overload , 2013, American journal of physiology. Heart and circulatory physiology.

[21]  Lei Zhong,et al.  The sirtuin SIRT6 blocks IGF-Akt signaling and development of cardiac hypertrophy by targeting c-Jun , 2012, Nature Medicine.

[22]  A. Benigni,et al.  Aging and the renin-angiotensin system. , 2012, Hypertension.

[23]  L. Young,et al.  AMP-Activated Protein Kinase Regulation and Biological Actions in the Heart , 2012, Circulation research.

[24]  P. Netti,et al.  Metformin Prevents the Development of Chronic Heart Failure in the SHHF Rat Model , 2012, Diabetes.

[25]  J. Hou.  Lecture , 2012 .

[26]  J. Bader,et al.  Functional dissection of lysine deacetylases reveals that HDAC1 and p300 regulate AMPK , 2011, Nature.

[27]  J. Sadoshima,et al.  PPARα-Sirt1 complex mediates cardiac hypertrophy and failure through suppression of the ERR transcriptional pathway. , 2011, Cell metabolism.

[28]  John M. Cunningham,et al.  The Deacetylase SIRT1 Promotes Membrane Localization and Activation of Akt and PDK1 During Tumorigenesis and Cardiac Hypertrophy , 2011, Science Signaling.

[29]  V. Dolinsky,et al.  Calorie Restriction Prevents Hypertension and Cardiac Hypertrophy in the Spontaneously Hypertensive Rat , 2010, Hypertension.

[30]  Jun Ren,et al.  AMP‐activated protein kinase deficiency exacerbates aging‐induced myocardial contractile dysfunction , 2010, Aging cell.

[31]  Jun Ren,et al.  Impaired Macrophage Migration Inhibitory Factor–AMP-Activated Protein Kinase Activation and Ischemic Recovery in the Senescent Heart , 2010, Circulation.

[32]  Y. Hayashi,et al.  Adiponectin and AdipoR1 regulate PGC-1α and mitochondria by Ca2+ and AMPK/SIRT1 , 2010, Nature.

[33]  J. Dyck,et al.  Cardiac-specific Deletion of LKB1 Leads to Hypertrophy and Dysfunction , 2009, The Journal of Biological Chemistry.

[34]  Gene Kim,et al.  Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. , 2009, The Journal of clinical investigation.

[35]  Sterling C. Johnson,et al.  Caloric Restriction Delays Disease Onset and Mortality in Rhesus Monkeys , 2009, Science.

[36]  S. Jha,et al.  Activation of AMP-Activated Protein Kinase by Metformin Improves Left Ventricular Function and Survival in Heart Failure , 2009, Circulation research.

[37]  G. Logroscino,et al.  Incidence of cardiovascular disease and cancer in advanced age: prospective cohort study , 2008, BMJ : British Medical Journal.

[38]  N. Ruderman,et al.  SIRT1 Modulation of the Acetylation Status, Cytosolic Localization, and Activity of LKB1 , 2008, Journal of Biological Chemistry.

[39]  Alexander S Banks,et al.  SirT1 gain of function increases energy efficiency and prevents diabetes in mice. , 2008, Cell metabolism.

[40]  E. Bober,et al.  Sirt7 Increases Stress Resistance of Cardiomyocytes and Prevents Apoptosis and Inflammatory Cardiomyopathy in Mice , 2008, Circulation research.

[41]  David A. Kass,et al.  Tackling heart failure in the twenty-first century , 2008, Nature.

[42]  Ruben Abagyan,et al.  Sirtuin 2 Inhibitors Rescue α-Synuclein-Mediated Toxicity in Models of Parkinson's Disease , 2007, Science.

[43]  S. Vatner,et al.  Sirt1 Regulates Aging and Resistance to Oxidative Stress in the Heart , 2007, Circulation research.

[44]  S. Klein,et al.  Aging, adiposity, and calorie restriction. , 2007, JAMA.

[45]  F. Alt,et al.  Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[46]  J. Denu,et al.  The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. , 2003, Molecular cell.

[47]  T. Mäkelä,et al.  Growth suppression by Lkb1 is mediated by a G(1) cell cycle arrest. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[48]  Ho-Shik Kim,et al.  Deletion of IGF-1 Receptors in Cardiomyocytes Attenuates Cardiac Aging in Male Mice. , 2016, Endocrinology.

[49]  英志 佐々木.  Metformin prevents progression of heart failure in dogs : role of AMP-activated protein kinase , 2009 .

[50]  K. Griendling,et al.  Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. , 2007, American journal of physiology. Cell physiology.

[51]  B. Thiers.  Genomic Instability and Aging-like Phenotype in the Absence of Mammalian SIRT6 , 2007 .