Son Ni-Huiping, Park Tae-Sik, Yamashita Haruyo, Yokoyama Masayoshi, Huggins Lesley A, Okajima Kazue, Homma Shunichi, Szabolcs Matthias J, Huang Li-Shin, Goldberg Ira J
Division of Preventive Medicine and Nutrition, Columbia University College of Physicians and Surgeons, New York, New York, USA.
J Clin Invest. 2007 Oct;117(10):2791-801. doi: 10.1172/JCI30335.
Three forms of PPARs are expressed in the heart. In animal models, PPARgamma agonist treatment improves lipotoxic cardiomyopathy; however, PPARgamma agonist treatment of humans is associated with peripheral edema and increased heart failure. To directly assess effects of increased PPARgamma on heart function, we created transgenic mice expressing PPARgamma1 in the heart via the cardiac alpha-myosin heavy chain (alpha-MHC) promoter. PPARgamma1-transgenic mice had increased cardiac expression of fatty acid oxidation genes and increased lipoprotein triglyceride (TG) uptake. Unlike in cardiac PPARalpha-transgenic mice, heart glucose transporter 4 (GLUT4) mRNA expression and glucose uptake were not decreased. PPARgamma1-transgenic mice developed a dilated cardiomyopathy associated with increased lipid and glycogen stores, distorted architecture of the mitochondrial inner matrix, and disrupted cristae. Thus, while PPARgamma agonists appear to have multiple beneficial effects, their direct actions on the myocardium have the potential to lead to deterioration in heart function.
三种形式的过氧化物酶体增殖物激活受体（PPARs）在心脏中表达。在动物模型中，PPARγ激动剂治疗可改善脂毒性心肌病；然而，PPARγ激动剂用于人类治疗时会伴有外周水肿和心力衰竭加重。为了直接评估PPARγ增加对心脏功能的影响，我们通过心脏α-肌球蛋白重链（α-MHC）启动子在心脏中创建了表达PPARγ1的转基因小鼠。PPARγ1转基因小鼠心脏中脂肪酸氧化基因的表达增加，脂蛋白甘油三酯（TG）摄取增加。与心脏PPARα转基因小鼠不同，心脏葡萄糖转运蛋白4（GLUT4）的mRNA表达和葡萄糖摄取并未降低。PPARγ1转基因小鼠发生了扩张型心肌病，伴有脂质和糖原储存增加、线粒体内基质结构扭曲以及嵴破坏。因此，虽然PPARγ激动剂似乎有多种有益作用，但其对心肌的直接作用有可能导致心脏功能恶化。
