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

Sundaresan, Nagalingam R.; Vasudevan, Prabhakaran; Zhong, Lei; Kim, Gene; Samant, Sadhana; Parekh, Vishwas; Pillai, Vinodkumar B.; Ravindra, P. V.; Gupta, Madhu; Jeevanandam, Valluvan; Cunningham, John M.; Deng, Chu Xia; Lombard, David B.; Mostoslavsky, Raúl; Gupta, Mahesh P.

doi:10.1038/nm.2961

Cited by 415 publications

(446 citation statements)

References 46 publications

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“…Furthermore, the inhibition of IGF-Akt signaling by SIRT6 has also been implicated in protection from cardiac hypertrophy, whereas deacetylation of H3K9 mediated by SIRT6 is crucial for transcriptional suppression of IGF signaling-related genes (17). In concordance with these reports, our experiments using mutant SIRT6 H133Y demonstrated that deacetylation of H3K9 by SIRT6 was necessary for attenuation of IGF-Akt-mTOR signaling, and that wild type SIRT6 tended to suppress IGF-1R expression levels in HBECs (Fig.…”

Section: Discussionsupporting

confidence: 87%

“…A recent study demonstrated that SIRT6 regulates IGF-Akt-mTOR signaling through the suppression of IGF signaling-related genes (17). We therefore investigated the involvement of SIRT6 in regulation of the IGF-Akt-mTOR signaling pathway by detecting phosphorylated forms of IGF-1R, Akt, and p70 S6Kinase (S6K, a downstream signaling molecule of mTOR).…”

Section: Sirt6 Attenuates the Igf-akt-mammalian Target Of Rapamycin Smentioning

confidence: 99%

“…Among the gene targeting models for seven mammalian sirtuins, SIRT6-deficient mice displayed a prominent premature aging phenotype accompanied by shortened life span (12,13). SIRT6 has been demonstrated to regulate longevity by a variety of mechanisms, including NF-kB inhibition, base excision repair, homologous recombination, and modulation of insulin-like growth factor (IGF)-I signaling (13)(14)(15)(16)(17)(18). Although IGF-I signaling has been reported to be involved in autophagy and cellular senescence (19), autophagy modulation by SIRT6 and implication of SIRT6 in regulation of cellular senescence during COPD pathogenesis remain to be elucidated.…”

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confidence: 99%

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Autophagy Induction by SIRT6 through Attenuation of Insulin-like Growth Factor Signaling Is Involved in the Regulation of Human Bronchial Epithelial Cell Senescence

Takasaka

Araya

Hara

et al. 2014

The Journal of Immunology

165

145

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Cigarette smoke (CS)–induced cellular senescence has been implicated in the pathogenesis of chronic obstructive pulmonary disease, and SIRT6, a histone deacetylase, antagonizes this senescence, presumably through the attenuation of insulin-like growth factor (IGF)-Akt signaling. Autophagy controls cellular senescence by eliminating damaged cellular components and is negatively regulated by IGF-Akt signaling through the mammalian target of rapamycin (mTOR). SIRT1, a representative sirtuin family, has been demonstrated to activate autophagy, but a role for SIRT6 in autophagy activation has not been shown. Therefore, we sought to investigate the regulatory role for SIRT6 in autophagy activation during CS-induced cellular senescence. SIRT6 expression levels were modulated by cDNA and small interfering RNA transfection in human bronchial epithelial cells (HBECs). Senescence-associated β-galactosidase staining and Western blotting of p21 were performed to evaluate senescence. We demonstrated that SIRT6 expression levels were decreased in lung homogenates from chronic obstructive pulmonary disease patients, and SIRT6 expression levels correlated significantly with the percentage of forced expiratory volume in 1 s/forced vital capacity. CS extract (CSE) suppressed SIRT6 expression in HBECs. CSE-induced HBEC senescence was inhibited by SIRT6 overexpression, whereas SIRT6 knockdown and mutant SIRT6 (H133Y) without histone deacetylase activity enhanced HBEC senescence. SIRT6 overexpression induced autophagy via attenuation of IGF-Akt-mTOR signaling. Conversely, SIRT6 knockdown and overexpression of a mutant SIRT6 (H133Y) inhibited autophagy. Autophagy inhibition by knockdown of ATG5 and LC3B attenuated the antisenescent effect of SIRT6 overexpression. These results suggest that SIRT6 is involved in CSE-induced HBEC senescence via autophagy regulation, which can be attributed to attenuation of IGF-Akt-mTOR signaling.

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Section: Discussionsupporting

confidence: 87%

Section: Sirt6 Attenuates the Igf-akt-mammalian Target Of Rapamycin Smentioning

confidence: 99%

mentioning

confidence: 99%

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Autophagy Induction by SIRT6 through Attenuation of Insulin-like Growth Factor Signaling Is Involved in the Regulation of Human Bronchial Epithelial Cell Senescence

Takasaka

Araya

Hara

et al. 2014

The Journal of Immunology

165

145

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“…26 High levels of IGF-1 have been associated with heart failure and increased cardiac mortality. 64,65 Thus, it is postulated that downregulation of Gab1 is a result of increased IGF-1. Alternatively, the loss of Gab1 may be due to increased degradation through the ubiquitin-proteasome system.…”

Section: Resultsmentioning

confidence: 99%

Cardiac Gab1 deletion leads to dilated cardiomyopathy associated with mitochondrial damage and cardiomyocyte apoptosis

et al. 2015

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A vital step in the development of heart failure is the transition from compensatory cardiac hypertrophy to decompensated dilated cardiomyopathy (DCM) during cardiac remodeling under mechanical or pathological stress. However, the molecular mechanisms underlying the development of DCM and heart failure remain incompletely understood. In the present study, we investigate whether Gab1, a scaffolding adaptor protein, protects against hemodynamic stress-induced DCM and heat failure. We first observed that the protein levels of Gab1 were markedly reduced in hearts from human patients with DCM and from mice with experimental viral myocarditis in which DCM developed. Next, we generated cardiac-specific Gab1 knockout mice (Gab1-cKO) and found that GabcKO mice developed DCM in hemodynamic stress-dependent and age-dependent manners. Under transverse aorta constriction (TAC), Gab1-cKO mice rapidly developed decompensated DCM and heart failure, whereas Gab1 wild-type littermates exhibited adaptive left ventricular hypertrophy without changes in cardiac function. Mechanistically, we showed that Gab1-cKO mouse hearts displayed severe mitochondrial damages and increased cardiomyocyte apoptosis. Loss of cardiac Gab1 in mice impaired Gab1 downstream MAPK signaling pathways in the heart under TAC. Gene profiles further revealed that ablation of Gab1 in heart disrupts the balance of anti-and pro-apoptotic genes in cardiomyocytes. These results demonstrate that cardiomyocyte Gab1 is a critical regulator of the compensatory cardiac response to aging and hemodynamic stress. These findings may provide new mechanistic insights and potential therapeutic target for DCM and heart failure. The progression of heart failure is associated with cardiac remodeling, the changes of cardiac structure and function in response to various stress conditions such as pressure overload-generated hemodynamic stress and agingassociated oxidative stress. 1 Under hemodynamic stress, the heart undergoes a stage of compensated hypertrophy and then progresses into decompensated dilated cardiomyopathy (DCM) and heart failure. 2 Cardiac hypertrophy is an adaptive, regulatory process, in which activation of cardiomyocyte survival pathways maintains cardiac homeostasis against external stress. During the transition from compensatory hypertrophy to DCM, cardiomyocyte death plays a critical role in development of heart failure. [3][4][5][6] However, the molecular mechanisms for controlling the balance of cell survival and cell death during cardiac remodeling remain poorly understood.The Grb2-associated binder 1 (Gab1) is a member of the insulin receptor substrate-like multi-substrate docking protein family and expressed in various types of cells, including cardiomyocytes. [7][8][9] It is a central mediator of growth factor receptor signaling. 10,11 Gab1 is phosphorylated by tyrosine kinases, and then phosphorylated Gab1 recruits and activates phosphatidylinositol 3-kinase (PI3K)/Akt and protein tyrosine phosphatase SHP2 (PTPN11)/mitogen-activated protein kinase (MAPK...

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“…Intriguingly, PTEN33 and CTMP exert the same effect in pathological cardiac hypertrophy induced by AngII. Except for CTMP, many molecules have been demonstrated to play crucial roles on cardiac remodeling induced by pressure overload by regulating AKT signaling 4, 35, 36, 37, 38, 39…”

Section: Discussionmentioning

confidence: 99%

Carboxyl‐Terminal Modulator Protein Ameliorates Pathological Cardiac Hypertrophy by Suppressing the Protein Kinase B Signaling Pathway

Liu

Yang

Zhu

et al. 2018

JAHA

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BackgroundCarboxyl‐terminal modulator protein (CTMP) has been implicated in cancer, brain injury, and obesity. However, the role of CTMP in pathological cardiac hypertrophy has not been identified.Methods and ResultsIn this study, decreased expression of CTMP was observed in both human failing hearts and murine hypertrophied hearts. To further explore the potential involvement of CTMP in pathological cardiac hypertrophy, cardiac‐specific CTMP knockout and overexpression mice were generated. In vivo experiments revealed that CTMP deficiency exacerbated the cardiac hypertrophy, fibrosis, and function induced by pressure overload, whereas CTMP overexpression alleviated the response to hypertrophic stimuli. Consistent with the in vivo results, adenovirus‐mediated gain‐of‐function or loss‐of‐function experiments showed that CTMP also exerted a protective effect against hypertrophic responses to angiotensin II in vitro. Mechanistically, CTMP ameliorated pathological cardiac hypertrophy through the blockade of the protein kinase B signaling pathway. Moreover, inhibition of protein kinase B activation with LY294002 rescued the deteriorated effect in aortic banding–treated cardiac‐specific CTMP knockout mice.ConclusionsTaken together, these findings imply, for the first time, that increasing the cardiac expression of CTMP may be a novel therapeutic strategy for pathological cardiac hypertrophy.

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

Cited by 415 publications

References 46 publications

Autophagy Induction by SIRT6 through Attenuation of Insulin-like Growth Factor Signaling Is Involved in the Regulation of Human Bronchial Epithelial Cell Senescence

Autophagy Induction by SIRT6 through Attenuation of Insulin-like Growth Factor Signaling Is Involved in the Regulation of Human Bronchial Epithelial Cell Senescence

Cardiac Gab1 deletion leads to dilated cardiomyopathy associated with mitochondrial damage and cardiomyocyte apoptosis

Carboxyl‐Terminal Modulator Protein Ameliorates Pathological Cardiac Hypertrophy by Suppressing the Protein Kinase B Signaling Pathway

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