PPARgamma signaling pathway in cardiac hypertrophy and failure

描述（由申请人提供）：心脏肥大是充血性心力衰竭的主要风险因素，充血性心力衰竭是许多心脏疾病的终末期疾病。心脏中氧化还原稳态的失调与心脏肥大和心力衰竭的发展有关。最近的研究表明，PPARgamma可能发挥抗肥大作用，其机制尚不清楚。我们的初步研究表明，心肌细胞限制性PPARgamma缺乏的小鼠在进行性心脏肥大和心力衰竭进展之前，其心脏中的超氧化物显着增加。我们假设，PPARgamma是一个重要的决定因素，心肌氧化还原稳态通过转录调节的关键内源性线粒体抗氧化剂，magenese，超氧化物歧化酶（SOD 2），在心脏，从而作为一个关键的调节心脏在各种病理生理条件。我们将使用体外，体内和离体方法的组合来测试我们的中心假设，即心脏PPARgamma通过激活SOD 2的表达来减少心肌细胞中有害的超氧化物，从而改善心肌细胞中的病理性左心室肥大反应。具体而言，我们将实现以下具体目标：目标1，确定PPARgamma如何在体外调节编码SOD 2的基因的表达;目标2，确定心肌细胞限制性敲除PPARgamma或过表达组成型活性PPARgamma的小鼠中心肌PPARgamma对SOD 2表达的影响;目的3，使用靶向诱导的心肌细胞限制性PPARgamma敲除小鼠来确定PPARgamma在从代偿性心脏肥大到心力衰竭的进展中的作用。我们还将确定SOD 2模拟药物是否改善或预防心肌细胞限制性PPARgamma敲除小鼠的进一步氧化损伤。我们将描述PPARgamma控制的抗氧化基因表达，心脏形态，活性氧的产生，心脏功能，心肌生物能量学和氧化损伤的PPARgamma转基因小鼠的心脏在心脏肥大和心力衰竭的发展过程中的压力超负荷。这些研究的结果应该提供新的机制调节心脏氧化还原稳态，从而提供新的见解，新的治疗目标，预防和治疗心脏肥大和心力衰竭。

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.