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Endocrinology. 2016 Jan;157(1):336-45. doi: 10.1210/en.2015-1709. Epub 2015 Oct 15.

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

Author information

1
Division of Endocrinology and Metabolism (S.O., J.A., H.M.K., J.K.), Department of Internal Medicine, Division of Cardiology (W.S.L.), Department of Internal Medicine, and Departments of Anesthesiology (H.K.) and Pathology (T.J.L.), College of Medicine, Chung-Ang University, Seoul, 156-755, Korea; Department of Biochemistry (H.-S.K.), College of Medicine, The Catholic University of Korea, Seoul, 110-758, Korea; Department of Surgery (D.J.), Vanderbilt University School of Medicine, Nashville, Tennessee 37232; and Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism (D.A.), University of Iowa Carver College of Medicine, Iowa City, Iowa 52242.

Abstract

IGF-1 receptor (IGF-1R) signaling is implicated in cardiac hypertrophy and longevity. However, the role of IGF-1R in age-related cardiac remodeling is only partially understood. We therefore sought to determine whether the deletion of the IGF-1R in cardiomyocytes might delay the development of aging-associated myocardial pathologies by examining 2-year-old male cardiomyocyte-specific IGF-1R knockout (CIGF1RKO) mice. Aging was associated with the induction of IGF-1R expression in hearts. Cardiomyocytes hypertrophied with age in wild-type (WT) mice. In contrast, the cardiac hypertrophic response associated with aging was blunted in CIGF1RKO mice. Concomitantly, fibrosis was reduced in aged CIGF1RKO compared with aged WT hearts. Expression of proinflammatory cytokines such as IL-1α, IL-1β, IL-6, and receptor activator of nuclear factor-κB ligand was increased in aged WT hearts, but this increase was attenuated in aged CIGF1RKO hearts. Phosphorylation of Akt was increased in aged WT, but not in aged CIGF1RKO, hearts. In cultured cardiomyocytes, IGF-1 induced senescence as demonstrated by increased senescence-associated β-galactosidase staining, and a phosphoinositide 3-kinase inhibitor inhibited this effect. Furthermore, inhibition of phosphoinositide 3-kinase significantly prevented the increase in IL-1α, IL-1β, receptor activator of nuclear factor-κB ligand, and p21 protein expression by IGF-1. These data reveal an essential role for the IGF-1-IGF-1R-Akt pathway in mediating cardiomyocyte senescence.

Comment in

PMID:
26469138
PMCID:
PMC4701888
DOI:
10.1210/en.2015-1709
[Indexed for MEDLINE]
Free PMC Article

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