PPARgamma signaling pathway in cardiac hypertrophy and failure

描述(申请人提供)：心脏肥厚是充血性心力衰竭的主要危险因素，充血性心力衰竭是一些心脏疾病的终末期状态。心脏氧化还原动态平衡的失调与心肌肥厚和心力衰竭的发生有关。最近的研究表明，PPARγ可能具有抗肥厚作用，其机制尚不清楚(S)。我们的初步研究显示，心肌细胞限制性PPARγ缺乏症小鼠在进行性心肌肥厚和进展为心力衰竭之前，心脏中的超氧化物歧化显著增加。我们推测，PPARGamma是心肌氧化还原动态平衡的重要决定因素，它通过转录调控心脏内关键的内源性线粒体抗氧化剂--Magenese，Superoxdismuase(SOD2)，从而在心脏对各种病理生理条件做出反应时发挥关键调节作用。我们将使用体外、体内和体外方法相结合的方法来验证我们的中心假设，即心脏PPARGamma通过激活SOD2的表达来减少心肌细胞中有害的超氧化物歧化，从而改善心肌细胞的病理性左心室肥厚反应。具体地说，我们将实现以下具体目标：目的1，确定PPARGamma如何在体外调控编码SOD2的基因的表达；目标2，确定心脏PPARGamma对心肌细胞限制性PPARGamma基因敲除或成分活性PPARGamma过表达的小鼠SOD2表达的影响；目标3，通过靶向诱导的PPARGamma基因敲除小鼠，确定PPARGamma在从代偿性心肌肥厚到心力衰竭进展中的作用。我们还将确定SOD2模拟药物是否改善或防止心肌细胞限制性PPAR伽马基因敲除小鼠的进一步氧化损伤。我们将对PPARGamma转基因小鼠在压力超负荷所致心肌肥大和心力衰竭发展过程中受控的抗氧化基因表达、心脏形态、活性氧产生、心脏功能、心肌生物能量学和氧化损伤进行研究。这些研究的结果将为心脏氧化还原动态平衡的调节提供新的机制，从而为预防和治疗心肌肥厚和心力衰竭的新的治疗靶点提供新的见解。

DESCRIPTION (provided by applicant): Cardiac hypertrophy is the main risk factor for congestive heart failure, which is the end-stage condition of a number of cardiac disorders. Deregulation of redox homeostasis in the heart has been implicated in the development of cardiac hypertrophy and heart failure. Recent studies suggest that PPARgamma may exert anti-hypertrophic effects with unknown mechanism(s). Our preliminary studies revealed that mice with - cardiomyocyte-restricted PPARgamma deficiency showed substantially increased superoxide in their heart prior to progressive cardiac hypertrophy and progression to heart failure. We postulate that PPARgamma is an essential determinant of myocardial redox homeostasis via transcriptional regulation of a key endogenous mitochondrial antioxidant, magenese, superoxide dismutase (SOD2), in the heart, thus serving as a pivotal regulator for the heart in response to various pathophysiological conditions. We will use a combination of in vitro, in vivo and ex vivo methods to test our central hypothesis that cardiac PPARgamma improves pathological left ventricular hypertrophic responses in cardiomyocytes by activating expression of SOD2 to diminish harmful superoxide in cardiomyocytes. Specifically, we will achieve the following specific aims: aim 1, to determine how PPARgamma regulates expression of genes encoding SOD2 in vitro; aim 2, to determine effects of cardiac PPARgamma on SOD2 expression in mice with either cardiomyocyte-restricted knockout of PPARgamma or overexpression of a constitutively active PPARgamma; aim 3, to define the role of PPARgamma in the progression from compensated cardiac hypertrophy to heart failure using a targeted inducible cardiomyocyte-restricted PPARgamma knockout mice. We will also determine if SOD2 mimetic drugs ameliorates or prevents further oxidative damage in the cardiomyocyte-restricted PPARgamma knockout mice. We will characterize PPARgamma controlled antioxidant gene expression, cardiac morphology, reactive oxygen species production, cardiac function, myocardial bioenergetics and oxidative damage in the heart of PPARgamma transgenic mice during the development of cardiac hypertrophy and heart failure induced by pressure-overload. Results from these studies should provide novel mechanisms on the regulation of cardiac redox homeostasis and hence provide new insights into novel therapeutic targets for the prevention and treatment of cardiac hypertrophy and heart failure.