Cardiomyocyte expression of PPARγ leads to cardiac dysfunction in mice
Cardiomyocyte expression of PPARγ leads to cardiac dysfunction in mice
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DOI：
10.1172/jci30335
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发表时间：
2007-10-01
影响因子：
15.9
通讯作者：
Goldberg, Ira J.
中科院分区：
文献类型：
--
作者：
Son, Ni-Huiping;Park, Tae-Sik;Goldberg, Ira J.
PPARs的三种形式在心脏中表达。在动物模型中，PPAR γ激动剂治疗可改善脂毒性心肌病;然而，人的PPAR γ激动剂治疗与外周水肿和心力衰竭增加相关。为了直接评估增加的PPARgamma对心脏功能的影响，我们通过心脏α-肌球蛋白重链（α-MHC）启动子在心脏中产生表达PPARgamma 1的转基因小鼠。PPAR γ 1转基因小鼠心脏脂肪酸氧化基因表达增加，脂蛋白甘油三酯（TG）摄取增加。与心脏PPAR α转基因小鼠不同，心脏葡萄糖转运蛋白4（GLUT 4）mRNA表达和葡萄糖摄取没有降低。PPARgamma 1转基因小鼠发生扩张型心肌病，与脂质和糖原储存增加、线粒体内基质结构扭曲和嵴破坏相关。因此，虽然PPAR γ激动剂似乎具有多种有益作用，但其对心肌的直接作用有可能导致心脏功能恶化。
Three forms of PPARs are expressed in the heart. In animal models, PPAR gamma agonist treatment improves lipotoxic cardiomyopathy; however, PPAR gamma agonist treatment of humans is associated with peripheral edema and increased heart failure. To directly assess effects of increased PPAR gamma on heart function, we created transgenic mice expressing PPAR gamma 1 in the heart via the cardiac cc-myosin heavy chain (alpha-MHC) promoter. PPAR gamma 1-transgenic mice had increased cardiac expression of fatty acid oxidation genes and increased lipoprotein triglyceride (TG) uptake. Unlike in cardiac PPAR alpha-transgenic mice, heart glucose transporter 4 (GLUT4) mRNA expression and glucose uptake were not decreased. PPAR gamma 1-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 PPAR gamma agonists appear to have multiple beneficial effects, their direct actions on the myocardium have the potential to lead to deterioration in heart function.