Ding Guoliang, Fu Mingui, Qin Qianhong, Lewis William, Kim Ha Won, Fukai Tohru, Bacanamwo Methode, Chen Yuqing Eugene, Schneider Michael D, Mangelsdorf David J, Evans Ronald M, Yang Qinglin
Cardiovascular Research Institute, Morehouse School of Medicine, 720 Westview Dr. SW, Atlanta, GA 30310, USA.
Cardiovasc Res. 2007 Nov 1;76(2):269-79. doi: 10.1016/j.cardiores.2007.06.027. Epub 2007 Jul 4.
Peroxisome proliferator-activated receptors (PPAR) alpha and beta/delta are essential transcriptional regulators of fatty acid oxidation in the heart. However, little is known about the roles of PPARgamma in the heart. The present study is to investigate in vivo role(s) of PPARgamma in the heart.
A Cre-loxP mediated cardiomyocyte-restricted PPARgamma knockout line was investigated. In these mice, exon 1 and 2 of PPARgamma were targeted to eliminate PPARgamma from cardiomyocytes.
PPARgamma null mice exhibited pathological changes around 3 months of age, featuring progressive cardiac hypertrophy with mitochondrial oxidative damage. Most mice died from dilated cardiomyopathy. Cardiac expression of Sod2 (encoding manganese superoxide dismutase; MnSOD), a mitochondrial antioxidant enzyme was downregulated both in transcript and protein levels in cardiac samples in PPARgamma knockout mice independent of pathological changes. Promoter analyses revealed that Sod2 is a target gene of PPARgamma. Consequently, myocardial superoxide content in PPARgamma knockout mice was increased, leading to extensive oxidative damage. Treatment with a SOD mimetic compound, MnTBAP, prevented superoxide-induced cardiac pathological changes in PPARgamma knockout mice.
The present study demonstrates that PPARgamma is critical to myocardial redox homeostasis. These findings should provide new insights into understanding the roles of PPARgamma in the heart.
过氧化物酶体增殖物激活受体（PPAR）α和β/δ是心脏脂肪酸氧化的重要转录调节因子。然而，关于PPARγ在心脏中的作用知之甚少。本研究旨在探讨PPARγ在心脏中的体内作用。
研究了一种Cre-loxP介导的心肌细胞特异性PPARγ基因敲除品系。在这些小鼠中，PPARγ的外显子1和2被靶向，以从心肌细胞中消除PPARγ。
PPARγ基因敲除小鼠在3个月大左右出现病理变化，表现为进行性心脏肥大并伴有线粒体氧化损伤。大多数小鼠死于扩张型心肌病。线粒体抗氧化酶Sod2（编码锰超氧化物歧化酶；MnSOD）在PPARγ基因敲除小鼠心脏样本中的转录和蛋白水平均下调，且与病理变化无关。启动子分析表明Sod2是PPARγ的靶基因。因此，PPARγ基因敲除小鼠心肌中超氧化物含量增加，导致广泛的氧化损伤。用超氧化物歧化酶模拟化合物MnTBAP治疗可预防PPARγ基因敲除小鼠中超氧化物诱导的心脏病理变化。
本研究表明PPARγ对心肌氧化还原稳态至关重要。这些发现应为理解PPARγ在心脏中的作用提供新的见解。
