PPAR-delta in Cardiac Hypertrophy and Heart Failure

心力衰竭是许多心脏疾病的终末期状态。心肌肥厚是主要的 心力衰竭的危险因素，过氧化物酶体增殖物激活受体(PPARα，-β和-γ)， 在调节脂类代谢基因方面起着重要作用。我们的实验室以前是基于对 一个独特的心肌细胞限制性PPARDelta基因敲除(CR-PPARDelta-/-)小鼠株系表明， PPARDelta亚型作为基础心肌脂肪酸氧化(FAO)的决定因素。这些研究 确定PPARDelta是心肌粮农组织的一个重要决定因素。最近的研究表明 PPARDelta的合成配体对培养的心肌细胞具有抗肥大作用。我们的预赛 研究表明，在肥厚的脑室中，PPARDelta的表达下调。此外, 培养心肌细胞PPARDelta激活和过表达抑制炎症反应 培养的心肌细胞。然而，目前尚不清楚PPARDelta是否在高血压患者中发挥抗肥厚作用。 对肥大刺激的反应。在这个拟议的项目中，我们将利用培养的心肌细胞系统 以及条件性心肌细胞特异性小鼠模型，以检验PPARDelta是一种 心脏生长的关键调节因子通过与其他转录因子的串扰反应肥大刺激 参与心脏生长的通路。我们将具体研究以下目标：确定是否 PPARDelta干扰其他信号通路影响培养的心肌细胞生长 确定PPARDelta在体内心肌肥厚发展中的作用；并确定 PPARDelta在从代偿性重构到心力衰竭进展中的作用。来自这些的结果 研究应该提供体内证据，证明PPARDelta作为心脏负调节因子的潜在作用 肥大的生长和进展为心力衰竭。对分子机制的进一步认识 心肌肥厚和心力衰竭的潜在发展应有助于提供新的治疗方法 治疗心力衰竭的靶点。

Heart failure is the end-stage condition of a number of cardiac disorders. Cardiac hypertrophy is the main risk factor for heart failure, peroxisome proliferator activated receptors (PPARalpha, -delta and -gamma), plays important roles in regulating lipid metabolic genes. Our laboratory has previously based on studies on a unique cardiomyocyte-restricted PPARdelta knockout (CR-PPARdelta-/-) mouse line demonstrated that the PPARdelta subtype as a determinant of basal myocardial fatty acid oxidation (FAO). These studies established that PPARdelta is an essential determinant of myocardial FAO. Recent studies suggest that synthetic ligands of PPARdelta exert anti-hypertrophic effects on cultured cardiomyocytes. Our preliminary studies indicated that PPARdelta expression is downregulated in hypertrophied ventricles. In addition, PPARdelta activation and overexpression in cultured cardiomyocytes suppressed inflammatory response in cultured cardiomyocytes. However, it remains unclear whether PPARdelta exerts anti-hypertrophic effects in response to hypertrophic stimuli. In this proposed project we will utilize the cultured cardiomyocyte system and the conditional cardiomyocyte-specific mouse models to test the central hypothesis that PPARdelta is a key regulator of cardiac growth in response to hypertrophic stimuli via crosstalks with other transcriptional pathways that are involved in cardiac growth. We will specifically study the following aims: to determine if PPARdelta interferes with other signaling pathways to influence cell growth of cultured cardiomyocytes in vitro; to determine the role of PPARdelta in the development of cardiac hypertrophy in vivo; and to determine the role of PPARdelta in the progression from compensated remodeling to heart failure. Results from these studies should provide in vivo evidence on a potential role of PPARdelta as a negative regulator of cardiac hypertrophic growth and progression to heart failure. Further understanding the molecular mechanisms underlying the development of cardiac hypertrophy and heart failure should help to provide novel therapeutic targets to treat heart failure.