The long-term objective of this application is to identify whether oxidative stress is responsible for the introduction of the phenotypic characteristics of the failing heart and whether interventions capable of interfering with the formation of reactive O2 modify the course of cardiac decompensation. Oxidative damage, mediated by activation of the local renin-angiotensin system (RAS) and enhanced by the reduction of nitric oxide (NO) in the stressed heart, may promote apoptotic and necrotic death of myocytes, endothelial cells, smooth muscle cells and fibroblasts. High levels of oxidative challenge trigger cell necrosis and lower levels induce apoptosis. Cardiac cell death results in loss of muscle, coronary arterioles and capillaries, which coupled with cavitary dilation and wall thinning, lead to defects in myocardial perfusion, ventricular dysfunction and ultimately heart failure (HF). Similar mechanisms may be operative in the diseased human heart during its evolution from moderate to severe decompensation and terminal failure, or in the aging mouse heart in which deletion of the eNOS gene should potentiate the effects of oxidative damage on cardiac cell death. Therefore, production of oxygen radicals may be the common denominator of several pathologic states of the heart including the development of the aging myopathy and HF in the elderly. Conversely, recovery from HF with removal of the inciting stimulus may initiate reactive growth restoring myocytes and vascular structures. Synthesis of NO, reduction of oxidative stress, downregulation of the cellular RAS, decreased cell death and attenuation of Ang II-induced myocyte hypertrophy may all contribute to the recovery process. It is postulated that significant regeneration of functioning myocardium is needed for regression of HF. Myocyte proliferation may be critical for the acute reconstitution of ventricular mass and, thereby, telomere length. Rapidly dividing cells may undergo progressive telomeric shortening, loss of DNA, terminal differentiation and growth arrest. These hypotheses will be tested in a model of HF associated with rapid ventricular pacing in dogs, in human hearts with idiopathic dilated cardiomyopathy in class I-IV NYHA and in an aging mouse model with ablation of the eNOS gene and greater potential for oxidative DNA damage and cardiac cell death.
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