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The sirtuin SIRT6 blocks IGF-Akt signaling and development of cardiac hypertrophy by targeting c-Jun

Nature Medicine volume 18, pages 1643–1650 (2012)Cite this article

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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.

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Figure 1: SIRT6 deficiency causes cardiac hypertrophy and degenerative changes in the heart.
Figure 2: Cardiac-specific deletion of SIRT6 causes cardiac hypertrophy and fibrosis.
Figure 3: SIRT6 overexpression blocks the cardiac hypertrophic response.
Figure 4: SIRT6 is a negative regulator of IGF signaling.
Figure 5: SIRT6 is a co-repressor of c-Jun transcriptional activity.
Figure 6: Inhibition of c-Jun or IGF signaling blocks hypertrophy of SIRT6-deficient hearts.

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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.

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Authors and Affiliations

  1. Department of Surgery, Committee on Cellular and Molecular Physiology, University of Chicago, Chicago, Illinois, USA

    Nagalingam R Sundaresan, Sadhana Samant, Vinodkumar B Pillai, P V Ravindra, Valluvan Jeevanandam & Mahesh P Gupta

  2. Department of Pediatrics, Committee on Developmental Biology, University of Chicago, Chicago, Illinois, USA

    Prabhakaran Vasudevan, Vishwas Parekh & John M Cunningham

  3. The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA

    Lei Zhong & Raul Mostoslavsky

  4. Department of Medicine, Section of Cardiology, University of Chicago, Chicago, Illinois, USA

    Gene Kim

  5. Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, Illinois, USA

    Madhu Gupta

  6. National Institute of Diabetes, Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, Maryland, USA

    Chu-Xia Deng

  7. Department of Pathology and Institute of Gerontology, University of Michigan, Ann Arbor, Michigan, USA

    David B Lombard

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  1. Nagalingam R Sundaresan
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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.

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Correspondence to Mahesh P Gupta.

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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

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