title: Diabetes promotes cardiac stem cell aging and heart failure, which are prevented by deletion of the p66shc gene.
abstract: Diabetes leads to a decompensated myopathy, but the etiology of the cardiac disease is poorly understood. Oxidative stress is enhanced with diabetes and oxygen toxicity may alter cardiac progenitor cell (CPC) function resulting in defects in CPC growth and myocyte formation, which may favor premature myocardial aging and heart failure. We report that in a model of insulin-dependent diabetes mellitus, the generation of reactive oxygen species (ROS) leads to telomeric shortening, expression of the senescent associated proteins p53 and p16INK4a, and apoptosis of CPCs, impairing the growth reserve of the heart. However, ablation of the p66shc gene prevents these negative adaptations of the CPC compartment, interfering with the acquisition of the heart senescent phenotype and the development of heart failure with diabetes. ROS elicit 3 cellular reactions: low levels activate cell growth, intermediate quantities trigger cell apoptosis, and high amounts initiate cell necrosis. CPC replication predominates in diabetic p66shc-/-, whereas CPC apoptosis and myocyte apoptosis and necrosis prevail in diabetic wild type. Expansion of CPCs and developing myocytes preserves cardiac function in diabetic p66shc-/-, suggesting that intact CPCs can effectively counteract the impact of uncontrolled diabetes on the heart. The recognition that p66shc conditions the destiny of CPCs raises the possibility that diabetic cardiomyopathy is a stem cell disease in which abnormalities in CPCs define the life and death of the heart. Together, these data point to a genetic link between diabetes and ROS, on the one hand, and CPC survival and growth, on the other.
authors.affiliation: Cardiovascular Research Institute, Department of Medicine, New York Medical College, Valhalla, NY 10595, USA.
authors.forename: Marcello
authors.initials: M
authors.lastname: Rota
authors.forename: Nicole
authors.initials: N
authors.lastname: LeCapitaine
authors.forename: Toru
authors.initials: T
authors.lastname: Hosoda
authors.forename: Alessandro
authors.initials: A
authors.lastname: Boni
authors.forename: Antonella
authors.initials: A
authors.lastname: De Angelis
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Padin-Iruegas
authors.forename: Grazia
authors.initials: G
authors.lastname: Esposito
authors.forename: Serena
authors.initials: S
authors.lastname: Vitale
authors.forename: Konrad
authors.initials: K
authors.lastname: Urbanek
authors.forename: Claudia
authors.initials: C
authors.lastname: Casarsa
authors.forename: Marco
authors.initials: M
authors.lastname: Giorgio
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
authors.forename: Pier Giuseppe
authors.initials: PG
authors.lastname: Pelicci
authors.forename: Piero
authors.initials: P
authors.lastname: Anversa
authors.forename: Annarosa
authors.initials: A
authors.lastname: Leri
authors.forename: Jan
authors.initials: J
authors.lastname: Kajstura
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D002303:Cardiac Output, Low / Q000209:etiology* / Q000517:prevention & control; D016923:Cell Death; D002455:Cell Division; D016922:Cellular Senescence; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D017353:Gene Deletion; D006321:Heart / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D017382:Reactive Oxygen Species; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1