PPARgamma signaling pathway cardiac hypertrophy/failure

描述（由申请人提供）：心脏肥厚是充血性心力衰竭的主要危险因素，充血性心力衰竭是许多心脏疾病的终末期状态。心脏氧化还原稳态的失调与心脏肥厚和心力衰竭的发生有关。最近的研究表明，PPARgamma可能具有抗肥厚作用，但机制未知。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心力衰竭进展之前，其心脏超氧化物含量显著增加。我们假设PPARgamma是心肌氧化还原稳态的重要决定因素，通过转录调节心脏中关键的内源性线粒体抗氧化剂，镁，超氧化物歧化酶（SOD2），从而作为心脏响应各种病理生理条件的关键调节因子。我们将结合体外、体内和离体方法来验证我们的中心假设，即心脏pppargamma通过激活SOD2的表达来减少心肌细胞中有害的超氧化物，从而改善心肌细胞的病理性左心室肥厚反应。具体而言，我们将实现以下具体目标：目标1，确定PPARgamma如何在体外调节SOD2编码基因的表达；目的2，在心肌细胞限制性敲除PPARgamma或过表达构成活性PPARgamma的小鼠中，确定心脏PPARgamma对SOD2表达的影响；目的3，利用靶向诱导心肌细胞受限的PPARgamma敲除小鼠，确定PPARgamma在代偿性心肌肥厚向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受限PPARgamma敲除小鼠的进一步氧化损伤。我们将研究PPARgamma转基因小鼠在压力过载引起的心脏肥大和心力衰竭过程中，PPARgamma控制的抗氧化基因表达、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。这些研究结果将为心脏氧化还原稳态调节提供新的机制，从而为预防和治疗心脏肥厚和心力衰竭提供新的治疗靶点。

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.