After myocardial infarction (MI) there is progressive remodeling of the remaining, viable left ventricular (LV) myocardium resulting in chamber dilation, pump dysfunction and clinical heart failure. LV remodeling is associated with profound molecular and cellular changes in myocytes including abnormal geometry, apoptosis and reversion to a fetal contractile phenotype. In vitro, nitric oxide (NO), superoxide (O2-) and their chemical product, peroxynitrite (ONOO-) mimic many of the molecular and cellular events observed in myocardial remodeling. NO and O2- are increased in failing myocardium in association with increased expression of NOS2 and decreased SOD activity. The investigators have shown that remodeling stimuli increase levels of NO and O2- in cardiac myocytes. Their central hypothesis is that NO and O2- exert deleterious effects on LV remodeling after MI by mediating the actions of remodeling stimuli on cardiac myocytes. By genetic and pharmacological manipulation of myocardial NO and O2-levels, the investigators will assess the roles of these chemicals in causing structural and functional remodeling in a mouse model of post-MI remodeling and failure. They propose a comprehensive, multidisciplinary approach utilizing studies at the whole animal, intact organ, isolated myocyte and molecular levels.
In Aims 1 and 2, the investigators will study LV remodeling in mice that lack inducible NO synthase (NOS2) or over-express manganese superoxide dismutase.
In Aims 3 and 4, they will test whether clinically-relevant treatment strategies that reduce myocardial NO and O2-can ameliorate post-MI remodeling, and thereby improve exercise function and survival.
In Aim 5, they will use in vivo and in vitro approaches to elucidate the mechanism responsible for increased o2-levels in the mouse heart post-MI, and to evaluate potential therapeutic strategies for use in Aim 3.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZHL1-CSR-F (S1))
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Reinlib, Leslie
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Boston University
Internal Medicine/Medicine
Schools of Medicine
United States
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