Diabetes Promotes Cardiac Stem Cell Aging and Heart Failure, Which Are Prevented by Deletion of the p66 ^shc Gene

Abstract

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 p16 INK4a , and apoptosis of CPCs, impairing the growth reserve of the heart. However, ablation of the p66 shc 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 p66shcϪ/Ϫ , whereas CPC apoptosis and myocyte apoptosis and necrosis prevail in diabetic wild type. Expansion of CPCs and developing myocytes preserves cardiac function in diabetic p66shcϪ/Ϫ , 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. Key Words: cardiac stem cells Ⅲ myocyte regeneration Ⅲ replicative senescence Ⅲ telomeric shortening D eath of cardiac cells with chronic loss of myocytes and vascular structures has been proposed as the underlying cause of the anatomical and functional alterations of the diabetic heart. 1 However, myocyte death and defects in the mechanical behavior, regulatory proteins, and Ca 2ϩ cycling of myocytes with diabetes have left unanswered the question of whether these variables play a primary role in the onset of the myopathy or represent secondary events related to the progression of the cardiac disease. Similar abnormalities occur with myocyte hypertrophy associated with ischemic and nonischemic cardiomyopathy, and myocyte death is commonly found in the failing heart. Accumulating evidence supports the notion that the heart possesses a compartment of multipotent progenitor cells (CPCs) that differentiate into myocytes, endothelial cells, and smooth muscle cells in vitro 2-4 and in vivo. 2 The heart constantly renews itself and an imbalance between cell death and regeneration may be present with diabetes and could be mediated by defects in growth and survival of CPCs.Hyperglycemia leads to enzymatic O-glycosylation of proteins, including the transcription factor p53, whose activation upregulates the local renin-angiotensin system and the synthesis of angiotensin II (Ang II)...

Significance of Endothelial Progenitor Cells in Subjects With Diabetes

“…Taken together, these data suggest that diabetic cardiomyopathy is a complex microvascular complication in which EPC deficiency may be one leading cause of the microcirculatory rarefaction that critically reduces myocardial perfusion. In addition to dysfunction of EPCs, oxidative stress-induced senescence of cardiomyocyte progenitors has been recognized as another potential underlying mechanism in diabetic cardiomyopathy (51). Interestingly, cardiac stem cell aging and heart failure associated with diabetes can be prevented by deletion of the stressrelated gene p66Shc, which we have shown to be potently upregulated in type 2 diabetic subjects (52).…”

Adoptive Transfer of Syngeneic Bone Marrow-Derived Cells in Mice with Obesity-Induced Diabetes

“…28 -30 It has recently been shown that diabetic state promotes aging of cardiac stem cells, a tissue resident stem cell population, and contribute to the heart failure. 31 We explored this hypothesis further in our BMDC transplant setting. Referring to the initial finding that the ScaIor Flk1-positive cell were decreased in BMDC of db/db Having demonstrated functional incompetence of BMDC obtained from db/db mice, we attempted to correct it using the selenoorganic antioxidant and peroxynitrite scavenger Ebs.…”

Number and function impairment of resident C-Kit+ cardiac stem cells in mice with renal dysfunction caused by 5/6 nephrectomy

“…21 Enhanced oxygen toxicity in diabetes alter the cardiac progenitor cell (CPC) function, and this effect is implemented via ROS-mediated telomere shortening and CPC apoptosis. 22 ROS also inhibits cellular adhesion of the engrafted mesenchymal stem cells implanted into ischemic myocardium. 23 The current study demonstrated that uremia decreased CSC number and reduced cytokine-stimulated angiogenesis.…”