This application raises the possibility that diabetes is a disease process that negatively affects the pool of cardiac progenitor cells (CPCs) through the activation of the cell death pathway and inhibition of cell replication. Diabetes impairs the growth reserve of the heart, so that enhanced cardiac cell death cannot be counteracted by repopulating myocytes and vascular cells and the preservation of the architecture and function of the myocardium. The loss in cell turnover alters myocardial homeostasis and favors cellular senescence and death. Diabetes is associated with an increased formation of reactive oxygen species (ROS), and the amount of ROS and the age of the cells may determine whether the death signal triggers apoptosis or necrosis of myocytes, smooth muscle cells (SMCs) and endothelial cells (ECs). However, an efficient regeneration of myocytes, SMCs and ECs by differentiation of CPCs should replace the lost cells and preserve the integrity of the myocardium. Unfortunately, CPCs cannot escape the consequences of diabetes. Attrition of the pool of CPCs leads to insufficient replacement of old, dying cells, and the acquisition of the heart senescent phenotype. ROS condition distinct forms of cell death; low quantities promote apoptosis and high quantities induce cell necrosis. The potentiated production of ROS and cellular senescence with diabetes may result in a shift in the pattern of cell death from apoptosis to necrosis. The latter promotes an inflammatory reaction, fibroblast activation, and myocardial scarring. Thus, diabetic cardiomyopathy is viewed as a stem cell myopathy in which a defective stem cell compartment conditions aging and death of myocytes, and vascular SMCs and ECs. Targeted mutation of the p66shc gene increases the resistance to oxidative stress and prolongs life in mice. This constitutes the first demonstration that a gene can modify the formation and effects of ROS on survival and maximum lifespan in mammals. For this reason, p66shc-/- mice will be studied to test the hypothesis that oxidative stress, cellular aging, and mechanisms of cell death are the critical determinants of the diabetic heart. If this were correct, the impact of ROS on the heart should be attenuated in p66shc-/- mice, delaying the onset of a diabetic myopathy. Most importantly, we may be able to identify a genetic link between diabetes and ROS, on the one hand, and premature cellular senescence and heart failure, on the other. ? ? ?
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