Abstract
Abnormal activation of insulin-like growth factor (IGF)-Akt signaling is implicated in the development of various diseases, including heart failure. However, the molecular mechanisms that regulate activation of this signaling pathway are not completely understood. Here we show that sirtuin 6 (SIRT6), a nuclear histone deacetylase, functions at the level of chromatin to directly attenuate IGF-Akt signaling. SIRT6-deficient mice developed cardiac hypertrophy and heart failure, whereas SIRT6 transgenic mice were protected from hypertrophic stimuli, indicating that SIRT6 acts as a negative regulator of cardiac hypertrophy. SIRT6-deficient mouse hearts showed hyperactivation of IGF signaling–related genes and their downstream targets. Mechanistically, SIRT6 binds to and suppresses the promoter of IGF signaling–related genes by interacting with c-Jun and deacetylating histone 3 at Lys9 (H3K9). We also found reduced SIRT6 expression in human failing hearts. These findings disclose a new link between SIRT6 and IGF-Akt signaling and implicate SIRT6 in the development of cardiac hypertrophy and failure.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Lloyd-Jones, D. et al. Heart disease and stroke statistics—2010 update: a report from the American Heart Association. Circulation 121, e46–e215 (2010).
Donmez, G. & Guarente, L. Aging and disease: connections to sirtuins. Aging Cell 9, 285–290 (2010).
Kahn, A.J. Development, aging, and life duration: effects of nutrient restriction. Am. J. Clin. Nutr. 25, 822–828 (1972).
Fontana, L., Partridge, L. & Longo, V.D. Extending healthy life span—from yeast to humans. Science 328, 321–326 (2010).
Weiss, E.P. & Fontana, L. Caloric restriction: powerful protection for the aging heart and vasculature. Am. J. Physiol. Heart Circ. Physiol. 301, H1205–H1219 (2011).
Haigis, M.C. & Guarente, L.P. Mammalian sirtuins—emerging roles in physiology, aging, and calorie restriction. Genes Dev. 20, 2913–2921 (2006).
Kanfi, Y. et al. SIRT6 protects against pathological damage caused by diet-induced obesity. Aging Cell 9, 162–173 (2010).
Kawahara, T.L. et al. SIRT6 links histone H3 lysine 9 deacetylation to NF-κB–dependent gene expression and organismal life span. Cell 136, 62–74 (2009).
Kim, H.S. et al. Hepatic-specific disruption of SIRT6 in mice results in fatty liver formation due to enhanced glycolysis and triglyceride synthesis. Cell Metab. 12, 224–236 (2010).
Michishita, E. et al. SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature 452, 492–496 (2008).
Michishita, E., Park, J.Y., Burneskis, J.M., Barrett, J.C. & Horikawa, I. Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Mol. Biol. Cell 16, 4623–4635 (2005).
Mostoslavsky, R. et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 124, 315–329 (2006).
Zhong, L. et al. The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1α. Cell 140, 280–293 (2010).
Xiao, C. et al. SIRT6 deficiency results in severe hypoglycemia by enhancing both basal and insulin-stimulated glucose uptake in mice. J. Biol. Chem. 285, 36776–36784 (2010).
Holzenberger, M. et al. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421, 182–187 (2003).
Matsui, T. et al. Phenotypic spectrum caused by transgenic overexpression of activated Akt in the heart. J. Biol. Chem. 277, 22896–22901 (2002).
Matsui, T., Nagoshi, T. & Rosenzweig, A. Akt and PI 3-kinase signaling in cardiomyocyte hypertrophy and survival. Cell Cycle 2, 220–223 (2003).
Kostin, S., Hein, S., Arnon, E., Scholz, D. & Schaper, J. The cytoskeleton and related proteins in the human failing heart. Heart Fail. Rev. 5, 271–280 (2000).
Sundaresan, N.R. et al. The deacetylase SIRT1 promotes membrane localization and activation of Akt and PDK1 during tumorigenesis and cardiac hypertrophy. Sci. Signal. 4, ra46–ra58 (2011).
Hess, J., Angel, P. & Schorpp-Kistner, M. AP-1 subunits: quarrel and harmony among siblings. J. Cell Sci. 117, 5965–5973 (2004).
Chiu, Y.C. et al. Peptidoglycan enhances IL-6 production in human synovial fibroblasts via TLR2 receptor, focal adhesion kinase, Akt, and AP-1–dependent pathway. J. Immunol. 183, 2785–2792 (2009).
Gallagher, E.J. & LeRoith, D. The proliferating role of insulin and insulin-like growth factors in cancer. Trends Endocrinol. Metab. 21, 610–618 (2010).
Gatenby, V.K. & Kearney, M.T. The role of IGF-1 resistance in obesity and type 2 diabetes-mellitus–related insulin resistance and vascular disease. Expert Opin. Ther. Targets 14, 1333–1342 (2010).
Glass, D.J. PI3 kinase regulation of skeletal muscle hypertrophy and atrophy. Curr. Top. Microbiol. Immunol. 346, 267–278 (2010).
Freude, S., Schilbach, K. & Schubert, M. The role of IGF-1 receptor and insulin receptor signaling for the pathogenesis of Alzheimer's disease: from model organisms to human disease. Curr. Alzheimer Res. 6, 213–223 (2009).
Haq, S. et al. Differential activation of signal transduction pathways in human hearts with hypertrophy versus advanced heart failure. Circulation 103, 670–677 (2001).
Chu, C.H. et al. Activation of insulin-like growth factor II receptor induces mitochondrial-dependent apoptosis through Gαq and downstream calcineurin signaling in myocardial cells. Endocrinology 150, 2723–2731 (2009).
Chao, W. & D'Amore, P.A. IGF2: epigenetic regulation and role in development and disease. Cytokine Growth Factor Rev. 19, 111–120 (2008).
Zaina, S. et al. Shortened life span, bradycardia, and hypotension in mice with targeted expression of an Igf2 transgene in smooth muscle cells. Endocrinology 144, 2695–2703 (2003).
Eferl, R. et al. Functions of c-Jun in liver and heart development. J. Cell Biol. 145, 1049–1061 (1999).
Schunkert, H., Jahn, L., Izumo, S., Apstein, C.S. & Lorell, B.H. Localization and regulation of c-fos and c-jun protooncogene induction by systolic wall stress in normal and hypertrophied rat hearts. Proc. Natl. Acad. Sci. USA 88, 11480–11484 (1991).
Iwaki, K., Sukhatme, V.P., Shubeita, H.E. & Chien, K.R. α- and β-adrenergic stimulation induces distinct patterns of immediate early gene expression in neonatal rat myocardial cells. fos/jun expression is associated with sarcomere assembly; Egr-1 induction is primarily an α 1–mediated response. J. Biol. Chem. 265, 13809–13817 (1990).
Takemoto, Y. et al. Increased JNK, AP-1 and NF-κB DNA binding activities in isoproterenol-induced cardiac remodeling. J. Mol. Cell. Cardiol. 31, 2017–2030 (1999).
Nadruz, W. Jr., Corat, M.A., Marin, T.M., Guimaraes Pereira, G.A. & Franchini, K.G. Focal adhesion kinase mediates MEF2 and c-Jun activation by stretch: role in the activation of the cardiac hypertrophic genetic program. Cardiovasc. Res. 68, 87–97 (2005).
Reiss, K. et al. ANG II receptors, c-myc, and c-jun in myocytes after myocardial infarction and ventricular failure. Am. J. Physiol. 264, H760–H769 (1993).
Freire, G., Ocampo, C., Ilbawi, N., Griffin, A.J. & Gupta, M. Overt expression of AP-1 reduces α myosin heavy chain expression and contributes to heart failure from chronic volume overload. J. Mol. Cell Cardiol. 43, 465–478 (2007).
Kim, H.J. et al. Modulation of redox-sensitive transcription factors by calorie restriction during aging. Mech. Ageing Dev. 123, 1589–1595 (2002).
Jung, K.J. et al. Effect of short term calorie restriction on pro-inflammatory NF-κB and AP-1 in aged rat kidney. Inflamm. Res. 58, 143–150 (2009).
Cohen, H.Y. et al. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 305, 390–392 (2004).
Kanfi, Y. et al. Regulation of SIRT6 protein levels by nutrient availability. FEBS Lett. 582, 543–548 (2008).
Hirschey, M.D. et al. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464, 121–125 (2010).
Sundaresan, N.R. et al. The deacetylase SIRT1 promotes membrane localization and activation of Akt and PDK1 during tumorigenesis and cardiac hypertrophy. Sci. Signal. 4, ra46 (2011).
Sundaresan, N.R. et al. Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. J. Clin. Invest. 119, 2758–2771 (2009).
Kanfi, Y. et al. The sirtuin SIRT6 regulates lifespan in male mice. Nature 483, 218–221 (2012).
Zhang, C.L. et al. Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy. Cell 110, 479–488 (2002).
Sundaresan, N.R., Samant, S.A., Pillai, V.B., Rajamohan, S.B. & Gupta, M.P. SIRT3 is a stress-responsive deacetylase in cardiomyocytes that protects cells from stress-mediated cell death by deacetylation of Ku70. Mol. Cell. Biol. 28, 6384–6401 (2008).
Pillai, J.B. et al. Activation of SIRT1, a class III histone deacetylase, contributes to fructose feeding-mediated induction of the α-myosin heavy chain expression. Am. J. Physiol. Heart Circ. Physiol. 294, H1388–H1397 (2008).
Wu, C.L., Kandarian, S.C. & Jackman, R.W. Identification of genes that elicit disuse muscle atrophy via the transcription factors p50 and Bcl-3. PLoS ONE 6, e16171 (2011).
Acknowledgements
We thank F. Alt, Harvard Medical School, for providing SIRT6 knockout mice, E. Verdin, University of California, San Francisco, for providing Flag-SIRT6 wild-type and mutant plasmids, F. VanGool, Institut de Biologie, Universite Libre de Bruxelles, Gosselies, Belgium, for providing mouse-SIRT6 expression plasmid and K. Chua, Stanford University, for providing SIRT6 retroviral vectors and SIRT6 knockout MEFs. The α-MHC promoter vector used to make cardiac-specific SIRT6 transgenic mice was provided by J. Robbins, University of Cincinnati. This study was supported by US National Institutes of Health grants RO1 HL-117041, HL-83423 and 111455 to M.P.G. N.R.S. was supported by a postdoctoral fellowship from the American Heart Association.
Author information
Authors and Affiliations
Contributions
N.R.S. and M.P.G. designed the study and wrote the manuscript. N.R.S. performed the majority of experiments. P.V. performed the ChIP experiments. L.Z. analyzed tissue microarray data. G.K. did echocardiography of mice. S.S. analyzed human samples and performed electron microscopy. V.P. performed in silico analysis and identified c-Jun target genes. V.B.P. performed experiments with IGF1R inhibitors. P.V.R. generated transgenic mice and did in vitro hypertrophy experiments. M.G. analyzed cardiac fetal gene program and cell death markers. V.J. provided human cardiac tissue samples during surgery. J.M.C. planned and supervised ChIP experiments. C.-X.D. provided Sirt6loxP mice. D.B.L. provided heart samples from SIRT6-MCK-Cre mice and participated in discussing experiments. R.M. provided microarray data and discussed the whole study multiple times. M.P.G. coordinated with different investigators, supervised the whole study and generated the final draft of the manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–15 and Supplementary Tables 1 and 2 (PDF 2455 kb)
Rights and permissions
About this article
Cite this article
Sundaresan, N., Vasudevan, P., Zhong, L. et al. The sirtuin SIRT6 blocks IGF-Akt signaling and development of cardiac hypertrophy by targeting c-Jun. Nat Med 18, 1643–1650 (2012). https://doi.org/10.1038/nm.2961
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nm.2961
This article is cited by
-
Epigenetics as a versatile regulator of fibrosis
Journal of Translational Medicine (2023)
-
Hallmarks of cardiovascular ageing
Nature Reviews Cardiology (2023)
-
Human centenarian–associated SIRT6 mutants modulate hepatocyte metabolism and collagen deposition in multilineage hepatic 3D spheroids
GeroScience (2023)
-
Sirt6 protects cardiomyocytes against doxorubicin-induced cardiotoxicity by inhibiting P53/Fas-dependent cell death and augmenting endogenous antioxidant defense mechanisms
Cell Biology and Toxicology (2023)
-
Metabolic Syndrome and Cardiac Remodeling Due to Mitochondrial Oxidative Stress Involving Gliflozins and Sirtuins
Current Hypertension Reports (2023)