MYOCARIDAL REMODELING BY HEMODYNAMIC OVERLOAD

高血压和心肌梗死（MI）是黑人心力衰竭的最常见原因，导致左心室（LV）血流动力学超负荷，从而启动心肌重塑过程。氧化应激在重塑心肌中增加，并且通过抗氧化剂阻止向衰竭的进展。我们发现，活性氧（ROS）和机械应变诱导心肌重塑的细胞标志，在体外心肌细胞肥大，胎儿基因表达和凋亡，并在心脏成纤维细胞的金属蛋白酶的激活。葡萄糖-6-磷酸脱氢酶（G6 PD）负责产生NADPH和维持还原型谷胱甘肽库，从而有助于降低细胞中ROS的水平。我们的中心假设是，ROS介导的心肌重塑响应血流动力学过载，G6 PD基因耗竭损害心肌的抗氧化能力，从而导致更迅速和有害的左心室重塑。我们将使用G6 PD缺陷小鼠来测试心肌G6 PD在确定血流动力学过载引起的心肌表型中的作用。在患有慢性高血压或MI的小鼠中，通过使用等容Langendorff制剂在高度受控条件下测量LV扩张和收缩功能，在器官水平评估心肌重塑。将通过超声心动图监测LV重构的时间进程。在组织水平，G6 PD缺乏的心肌效应将通过测量肌细胞尺寸、胎儿基因表达、细胞凋亡和金属蛋白酶的活化来评估。我们将使用从新生小鼠心脏培养的心肌细胞和成纤维细胞作为体外系统，以进一步研究G6 PD在确定细胞的抗氧化能力，对机械应变和定义的ROS的表型反应，以及潜在的治疗方法的功效中的作用。这些实验将阐明G6 PD在病理性心肌重塑中的作用，并提出可能的治疗策略。

Hypertension and myocardial infarction (MI), the most common causes of heart failure in blacks, result in hemodynamic overload of the left ventricle (LV) thereby initiating the process of myocardial remodeling. Oxidative stress is increased in remodeling myocardium, and the progression to failure is prevented by antioxidants. We found that reactive oxygen species (ROS) and mechanical strain induce the cellular hallmarks of myocardial remodeling in vitro-hypertrophy, fetal gene expression and apoptosis in cardiac myocytes, and activation of metalloproteinases in cardiac fibroblasts. Glucose-6-phosphate dehydrogenase (G6PD) is responsible for generation of NADPH and maintenance of the reduced glutathione pool, and thereby helps to reduce the level of ROS in the cell. Our central hypothesis is that ROS mediate myocardial remodeling in response to hemodynamic overload, and that genetic depletion of G6PD impairs the antioxidant capacity of the myocardium thereby leading to more rapid and deleterious LV remodeling. We will use G6PD-deficient mice to test the role of myocardial G6PD in determining the myocardial phenotypes caused by hemodynamic overload. In mice with chronic hypertension or MI, myocardial remodeling will be assessed at the organ level by measuring LV dilation and contractile function under highly controlled conditions using the isovolumic, Langendorff preparation. The temporal course of LV remodeling will be monitored by echocardiography. At the tissue level, the myocardial effects of G6PD deficiency will be assessed by measuring myocyte dimensions, fetal gene expression, apoptosis, and the activation of metalloproteinases. We will use cardiac myocytes and fibroblasts cultured from neonatal mouse hearts as in vitro system to examine further the role of G6PD in determining the antioxidant capacity of the cell, the phenotypic responses to mechanic strain and defined ROS, and the efficacy of potential therapeutic approaches. There experiments will elucidate the role of G6PD in pathologic myocardial remodeling, and suggest possible therapeutic strategies.