Nitric oxide synthase 3 and left ventricular remodeling

描述(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态变化和肥厚。在某些情况下，进行性左室重构会导致收缩功能恶化，导致充血性心力衰竭和死亡。一氧化氮(NO)的产生变化与心脏重塑的发病机制有关。首席研究员已经组建了一个多学科的科学家团队，目的是阐明三种一氧化氮合酶(NOS)亚型中的一种，NOS3，在左室重构中的作用。研究人员观察到，在NOS3缺乏的小鼠中，冠状动脉闭塞后的左室重构比野生型小鼠更严重。这种效应与NOS3缺陷小鼠的血压升高无关，与非梗死心肌中心肌细胞肥大的增加有关。本申请中提出的研究目的是了解NOS3是如何限制心室重构的。首先，在野生型和NOS3缺陷小鼠中，参与心肌细胞肥大和与左室重构相关的细胞凋亡的信号转导通路将是特征。其次，NOS3在其他血流动力学挑战引起的左室重构中的作用将通过压力和容量超负荷的小鼠模型来检验。第三，将使用转基因和基因转移的方法来确定增加小鼠心脏NOS3的表达是否可以减轻心肌梗死后的左室重构。最后，cGMP是NOS3/NO信号的重要介导者，在限制心肌梗死后左室重构中的作用将通过小鼠心脏特异表达的转基因来阐明，这些转基因旨在抑制NO刺激的cGMP合成或增强cGMP的代谢。目前针对预防和治疗心肌梗死后左室重构的治疗方法并不统一有效。进一步了解NOS3在心室重构中的作用可能会导致开发新的治疗方法来预防心梗后充血性心力衰竭及其相关的发病率和死亡率。

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.