MYOCARIDAL REMODELING BY HEMODYNAMIC OVERLOAD

高血压和心肌梗死（MI）是黑人心力衰竭最常见的原因，导致左心室（LV）血流动力学超载，从而启动心肌重构过程。氧化应激在心肌重塑过程中增加，抗氧化剂可以防止心肌衰竭。我们发现活性氧（ROS）和机械应变可诱导体外心肌肥厚重构、心肌细胞胎儿基因表达和凋亡以及心肌成纤维细胞金属蛋白酶的激活。葡萄糖-6-磷酸脱氢酶（G6PD）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内ROS的水平。我们的中心假设是，ROS介导心肌重构以应对血流动力学超载，G6PD的基因缺失会损害心肌的抗氧化能力，从而导致更快和更有害的左室重构。我们将使用G6PD缺陷小鼠来测试心肌G6PD在确定血流动力学过载引起的心肌表型中的作用。对于患有慢性高血压或心肌梗死的小鼠，在高度控制的条件下，使用等容Langendorff制剂，通过测量左室扩张和收缩功能，在器官水平上评估心肌重构。超声心动图监测左室重构的时间进程。在组织水平上，G6PD缺乏对心肌的影响将通过测量心肌细胞尺寸、胎儿基因表达、细胞凋亡和金属蛋白酶的激活来评估。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，进一步研究G6PD在决定细胞抗氧化能力、机械应变和定义ROS的表型反应以及潜在治疗方法的功效方面的作用。这些实验将阐明G6PD在病理性心肌重构中的作用，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.