PPAR-delta in Cardiac Hypertrophy and Heart Failure

心力衰竭是许多心脏疾病的终末期病症。心脏肥大是主要的 心力衰竭的危险因素，过氧化物酶体增殖物激活受体（PPARalpha，-δ和-γ）， 在调节脂质代谢基因中起重要作用。我们的实验室以前曾根据对 一种独特的心肌细胞限制性PPARdelta敲除（CR-PPARdelta-/-）小鼠系证明， PPARdelta亚型作为基础心肌脂肪酸氧化（FAO）的决定因素。这些研究 证实了PPARdelta是心肌FAO的重要决定因素。最近的研究表明， 合成的PPAR δ配体对培养的心肌细胞发挥抗肥大作用。我们的初步 研究表明，在肥大的心室中，PPAR δ表达下调。此外，本发明还提供了一种方法， 在培养的心肌细胞中激活和过表达PPARdelta抑制炎症反应， 培养的心肌细胞然而，目前尚不清楚PPARdelta是否在心肌细胞中发挥抗肥大作用。 对肥大刺激的反应。在这个项目中，我们将利用培养的心肌细胞系统， 和条件性心肌细胞特异性小鼠模型，以检验PPARdelta是一种心肌细胞特异性受体的中心假设。 通过与其他转录因子的交叉作用对肥大刺激作出反应的心脏生长的关键调节因子 参与心脏生长的途径。我们将具体研究以下目标： PPARdelta干扰其他信号通路影响培养心肌细胞的细胞生长 体外;确定PPARdelta在体内心脏肥大发展中的作用;并确定 PPARdelta在从代偿性重构到心力衰竭的进展中的作用。从这些 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。 肥大性生长并进展为心力衰竭。进一步了解分子机制 潜在的心脏肥大和心力衰竭的发展应有助于提供新的治疗方法， 治疗心力衰竭的目标。

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.