Nitric oxide synthase 3 and left ventricular remodeling

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DESCRIPTION (provided by applicant): After myocardial infarction (MI), the compensatory response of the left ventricle (LV) includes changes in shape and hypertrophy of the non-infarcted myocardium. In some cases, progressive LV remodeling causes deterioration of contractile function leading to congestive heart failure and death. Altered nitric oxide (NO) production has been implicated in the pathogenesis of cardiac remodeling. The principal investigator has assembled a multidisciplinary team of scientists with the objective of elucidating the role of one of the three NO synthase (NOS) isoforms, NOS3, in LV remodeling. The investigators observed that LV remodeling following coronary artery occlusion was greater in mice deficient in NOS3 than in wild-type mice. This effect was independent of the increased blood pressure observed in NOS3-deficient mice and was associated with increased cardiac myocyte hypertrophy in the non-infarcted myocardium. The objective of the research proposed in this application is to understand how NOS3 limits ventricular remodeling. First, the signal transduction pathways that participate in myocyte hypertrophy and apoptosis associated with LV remodeling will be characterized in wild type and NOS3-deficient mice. Second, the role of NOS3 in the LV remodeling caused by other hemodynamic challenges will be examined using murine models of pressure- and volume-overload. Third, transgenic and gene transfer approaches will be used to determine if augmentation of cardiac NOS3 expression in mice attenuates LV remodeling after MI. Finally, the role of cGMP, an important mediator of NOS3/NO signaling, in limiting LV remodeling after MI will be elucidated using mice with cardiac-specific expression of transgenes designed to inhibit NO-stimulated cGMP synthesis or to augment cGMP metabolism. Current therapies directed at prevention and treatment of LV remodeling after MI are not uniformly effective. Improved understanding of the role of NOS3 in ventricular remodeling may lead to the development of novel therapeutic approaches to preventing congestive heart failure and its associated morbidity and mortality after MI.