Nitric oxide synthase 3 and left ventricular remodeling

描述（由申请人提供）：心肌梗死（MI）后，左心室（LV）的代偿反应包括非梗死心肌的形状变化和肥大。 在某些情况下，进行性LV重构导致收缩功能恶化，从而导致充血性心力衰竭和死亡。 一氧化氮（NO）的产生改变与心脏重塑的发病机制有关。 主要研究者组建了一个多学科的科学家团队，目的是阐明三种NO合酶（NOS）亚型之一NOS 3在LV重塑中的作用。 研究人员观察到，在冠状动脉闭塞后，NOS 3缺陷小鼠的LV重塑比野生型小鼠更严重。 这种效应与在NOS 3缺陷小鼠中观察到的血压升高无关，并且与非梗死心肌中心肌细胞肥大增加有关。 本申请中提出的研究目的是了解NOS 3如何限制心室重塑。 首先，参与与LV重构相关的肌细胞肥大和凋亡的信号转导途径将在野生型和NOS 3缺陷小鼠中表征。 其次，将使用压力和容量超负荷的鼠模型来检查NOS 3在由其他血液动力学挑战引起的LV重构中的作用。 第三，转基因和基因转移的方法将被用来确定是否增加心脏NOS 3的表达在小鼠减轻心肌梗死后左心室重塑。 最后，cGMP的作用，一个重要的调解人的NOS 3/NO信号，在限制心肌梗死后左心室重塑将阐明使用小鼠心脏特异性表达的转基因设计来抑制NO刺激cGMP合成或增加cGMP代谢。 目前针对预防和治疗MI后LV重塑的疗法并不一致有效。 对NOS 3在心室重构中作用的进一步了解可能会导致新的治疗方法的发展，以预防充血性心力衰竭及其相关的发病率和死亡率后MI。

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.