Deletion of IGF-1 Receptors in Cardiomyocytes Attenuates Cardiac Aging in Male Mice

Ock, Sangmi; Lee, Wang Soo; Ahn, Jeongmin; Kim, Hyun Min; Kang, Hyun; Kim, Ho Shik; Jo, Daewoong; Abel, E. Dale; Lee, Tae Jin; Kim, Jaetaek

doi:10.1210/en.2015-1709

Cited by 80 publications

(62 citation statements)

References 47 publications

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“…In accordance with the RNA-seq results, we did not find any significant differences in the levels of secreted proteins using a cytokine array ( Fig 4F). Our data are in contrast with a previous report that shows increased expression of SASP components in murine heart with age using whole heart homogenates (Ock et al, 2016). We therefore compared the expression of previously reported SASP components in non-purified and purified CM populations.…”

Section: Aged Cardiomyocytes Activate Senescence Pathways But Not a Tcontrasting

confidence: 99%

Length‐independent telomere damage drives post‐mitotic cardiomyocyte senescence

et al. 2019

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Ageing is the biggest risk factor for cardiovascular disease. Cellular senescence, a process driven in part by telomere shortening, has been implicated in age‐related tissue dysfunction. Here, we address the question of how senescence is induced in rarely dividing/post‐mitotic cardiomyocytes and investigate whether clearance of senescent cells attenuates age‐related cardiac dysfunction. During ageing, human and murine cardiomyocytes acquire a senescent‐like phenotype characterised by persistent DNA damage at telomere regions that can be driven by mitochondrial dysfunction and crucially can occur independently of cell division and telomere length. Length‐independent telomere damage in cardiomyocytes activates the classical senescence‐inducing pathways, p21CIP and p16INK4a, and results in a non‐canonical senescence‐associated secretory phenotype, which is pro‐fibrotic and pro‐hypertrophic. Pharmacological or genetic clearance of senescent cells in mice alleviates detrimental features of cardiac ageing, including myocardial hypertrophy and fibrosis. Our data describe a mechanism by which senescence can occur and contribute to age‐related myocardial dysfunction and in the wider setting to ageing in post‐mitotic tissues.

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Section: Aged Cardiomyocytes Activate Senescence Pathways But Not a Tcontrasting

confidence: 99%

Length‐independent telomere damage drives post‐mitotic cardiomyocyte senescence

et al. 2019

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“…Our data are in contrast with a previous report that shows increased expression of SASP components in murine heart with age using whole heart homogenates (Ock, Lee et al, 2016). We therefore compared the expression of previously reported SASP components in non-purified and purified CM populations.…”

Section: Aged Cardiomyocytes Activate Senescent Pathways But Not a Tycontrasting

confidence: 99%

Length-independent telomere damage drives cardiomyocyte senescence

Anderson

Lagnado

Maggiorani

et al. 2018

Preprint

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Ageing is the biggest risk factor for cardiovascular health and is associated with increased incidence of cardiovascular disease. Cellular senescence, a process driven in part by telomere shortening, has been implicated in age-related tissue dysfunction. Here, we address the question of how senescence is induced in rarely dividing/post-mitotic cardiomyocytes and investigate if clearance of senescent cells attenuates age related cardiac dysfunction. During ageing, human and murine cardiomyocytes acquire a senescentlike phenotype characterised by persistent DNA damage at telomere regions that can be driven by mitochondrial dysfunction, and crucially can occur independently of cell-division and telomere length. Length-independent telomere damage in cardiomyocytes activates the classical senescence-inducing pathways, p21 CIP and p16 INK4a and results in a non-canonical senescence-associated secretory phenotype. Pharmacological or genetic clearance of senescent cells in mice alleviates myocardial hypertrophy and fibrosis, detrimental features . CC-BY-NC-ND 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

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“…12, 19–21 Therefore, these core metabolic regulators were analyzed in the hearts of aged WT and Sirt2 -KO mice. IGF1R phosphorylation at Tyr1135 and SIRT1 expression were comparable in the hearts of aged WT and Sirt2 KO mice.…”

Section: Resultsmentioning

confidence: 99%

SIRT2 Acts as a Cardioprotective Deacetylase in Pathological Cardiac Hypertrophy

et al. 2017

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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 (WT) and Sirt2 knockout (Sirt2-KO) mice were subjected to the investigation of aging-related cardiac hypertrophy. Cardiac hypertrophy was also induced by Ang II (1.3 mg/kg/day for four weeks) in male C57BL/6J Sirt2-KO mice, cardiac-specific SIRT2 transgenic (SIRT2-Tg) mice and their respective littermates (8~12-week-old). Metformin (200 mg/kg/day) was used to treat WT and Sirt2-KO mice that were infused with Ang II. Cardiac hypertrophy, fibrosis, and cardiac function were examined in these mice. Results SIRT2 protein expression levels were down-regulated in hypertrophic hearts from mice. Sirt2-KO markedly exaggerated cardiac hypertrophy and fibrosis as well as decreases in 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.

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Deletion of IGF-1 Receptors in Cardiomyocytes Attenuates Cardiac Aging in Male Mice

Cited by 80 publications

References 47 publications

Length‐independent telomere damage drives post‐mitotic cardiomyocyte senescence

Length‐independent telomere damage drives post‐mitotic cardiomyocyte senescence

Length-independent telomere damage drives cardiomyocyte senescence

SIRT2 Acts as a Cardioprotective Deacetylase in Pathological Cardiac Hypertrophy

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