Differential roles of cardiomyocyte and macrophage peroxisome proliferator-activated receptor gamma in cardiac fibrosis.
Differential roles of cardiomyocyte and macrophage peroxisome proliferator-activated receptor gamma in cardiac fibrosis.
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作者：
Caglayan E;Stauber B;Collins AR;Lyon CJ;Yin F;Liu J;Rosenkranz S;Erdmann E;Peterson LE;Ross RS;Tangirala RK;Hsueh WA
心脏纤维化是糖尿病性心肌病的重要组成部分。过氧化物酶体增殖物激活受体γ（PPARγ）配体抑制促炎基因表达，包括骨桥蛋白的表达，骨桥蛋白是心肌纤维化发展的已知贡献者。因此，我们研究了过氧化物酶体增殖物激活受体γ配体可以减轻心脏纤维化的假设。研究设计和方法-野生型心肌细胞和巨噬细胞特异性PPARγ−/−小鼠输注血管紧张素II（AngII）以促进心脏纤维化，并用PPARγ配体吡格列酮治疗以确定心肌细胞和巨噬细胞PPARγ在心脏纤维化中的作用。ACS-心肌细胞特异性PPARγ−/−小鼠（cPPARγ−/−）出现自发性心脏肥大，心室骨桥蛋白表达和巨噬细胞含量增加，AngII输注加重了这种情况。吡格列酮减弱了野生型和cPPARγ−/−小鼠中AngII诱导的纤维化、巨噬细胞蓄积和骨桥蛋白表达，但以PPARγ依赖性方式诱导肥大。我们采用两种机制来解释吡格列酮的抗纤维化心肌细胞-PPAR γ非依赖性作用：增加脂联素表达和减弱促炎巨噬细胞活性。腺病毒表达的脂联素对心肌纤维化没有影响，而PPARγ配体吡格列酮并没有减弱血管紧张素II诱导的心肌纤维化、骨桥蛋白表达或单核细胞特异性PPARγ−/−小鼠中的巨噬细胞蓄积。结论-我们得出以下结论：1）心肌细胞特异性的PPARγ缺乏和激活均促进心脏肥大，2）心肌细胞和单核细胞的PPARγ均调节心脏巨噬细胞浸润，3）炎症是AngII诱导的心脏纤维化的关键介质，4）巨噬细胞的PPARγ激活防止心肌巨噬细胞积聚，5）PPARγ配体通过抑制心肌巨噬细胞浸润减轻AngII诱导的心肌纤维化。这些观察结果对预防心脏纤维化的潜在干预措施具有重要意义。
OBJECTIVE—Cardiac fibrosis is an important component of diabetic cardiomyopathy. Peroxisome proliferator–activated receptor γ (PPARγ) ligands repress proinflammatory gene expression, including that of osteopontin, a known contributor to the development of myocardial fibrosis. We thus investigated the hypothesis that PPARγ ligands could attenuate cardiac fibrosis. RESEARCH DESIGN AND METHODS—Wild-type cardiomyocyte- and macrophage-specific PPARγ−/− mice were infused with angiotensin II (AngII) to promote cardiac fibrosis and treated with the PPARγ ligand pioglitazone to determine the roles of cardiomyocyte and macrophage PPARγ in cardiac fibrosis. RESULTS—Cardiomyocyte-specific PPARγ−/− mice (cPPARγ−/−) developed spontaneous cardiac hypertrophy with increased ventricular osteopontin expression and macrophage content, which were exacerbated by AngII infusion. Pioglitazone attenuated AngII-induced fibrosis, macrophage accumulation, and osteopontin expression in both wild-type and cPPARγ−/− mice but induced hypertrophy in a PPARγ-dependent manner. We pursued two mechanisms to explain the antifibrotic cardiomyocyte-PPARγ–independent effects of pioglitazone: increased adiponectin expression and attenuation of proinflammatory macrophage activity. Adenovirus-expressed adiponectin had no effect on cardiac fibrosis and the PPARγ ligand pioglitazone did not attenuate AngII-induced cardiac fibrosis, osteopontin expression, or macrophage accumulation in monocyte-specific PPARγ−/− mice. CONCLUSIONS—We arrived at the following conclusions: 1) both cardiomyocyte-specific PPARγ deficiency and activation promote cardiac hypertrophy, 2) both cardiomyocyte and monocyte PPARγ regulate cardiac macrophage infiltration, 3) inflammation is a key mediator of AngII-induced cardiac fibrosis, 4) macrophage PPARγ activation prevents myocardial macrophage accumulation, and 5) PPARγ ligands attenuate AngII-induced cardiac fibrosis by inhibiting myocardial macrophage infiltration. These observations have important implications for potential interventions to prevent cardiac fibrosis.
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影响因子：
8.3
作者：
Engeli, S;Bohnke, J;Sharma, AM
通讯作者：
Sharma, AM
影响因子：
15.9
作者：
Bruemmer, D;Collins, AR;Hsueh, WA
通讯作者：
Hsueh, WA
DOI：
10.1111/j.1749-6632.1999.tb07789.x
发表时间：
1999-01-01
期刊：
THE METABOLIC SYNDROME X
影响因子：
--
作者：
Daugherty, A;Cassis, L
通讯作者：
Cassis, L
影响因子：
5
作者：
Kintscher, U;Goetze, S;Law, RE
通讯作者：
Law, RE
影响因子：
3
作者：
Clausen, BE;Burkhardt, C;Förster, I
通讯作者：
Förster, I