title: Deletion of IGF-1 Receptors in Cardiomyocytes Attenuates Cardiac Aging in Male Mice.
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.
authors.affiliation: 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.
authors.forename: Sangmi
authors.initials: S
authors.lastname: Ock
authors.affiliation: 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.
authors.forename: Wang Soo
authors.initials: WS
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Jihyun
authors.initials: J
authors.lastname: Ahn
authors.affiliation: 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.
authors.forename: Hyun Min
authors.initials: HM
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Hyun
authors.initials: H
authors.lastname: Kang
authors.affiliation: 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.
authors.forename: Ho-Shik
authors.initials: HS
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Daewoong
authors.initials: D
authors.lastname: Jo
authors.affiliation: 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.
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
authors.affiliation: 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.
authors.forename: Tae Jin
authors.initials: TJ
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Jaetaek
authors.initials: J
authors.lastname: Kim
mesh_terms: D000375:Aging; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D006332:Cardiomegaly / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005355:Fibrosis; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D015415:Biomarkers; D016207:Cytokines; D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; C548904:insulin-like growth factor-1, rat; D007334:Insulin-Like Growth Factor I; D058539:Phosphatidylinositol 3-Kinase; D017526:Receptor, IGF Type 1; C494920:Akt1 protein, rat; D051057:Proto-Oncogene Proteins c-akt