Transforming growth factor-β inhibits myocardial PPARγ expression in pressure overload-induced cardiac fibrosis and remodeling in mice.
Transforming growth factor-β inhibits myocardial PPARγ expression in pressure overload-induced cardiac fibrosis and remodeling in mice.
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DOI：
10.1097/hjh.0b013e32834a4d03
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发表时间：
2011-09
影响因子：
4.9
通讯作者：
Xing D
中科院分区：
文献类型：
--
作者：
Gong K;Chen YF;Li P;Lucas JA;Hage FG;Yang Q;Nozell SE;Oparil S;Xing D
过氧化物酶体增殖物激活受体γ（过氧化物酶体增殖物激活受体γ）的药理学激活已被证明可以减轻压力超负荷诱导的心脏纤维化，表明过氧化物酶体增殖物激活受体γ具有抗纤维化作用。本研究验证了转化生长因子-β（TGF-β）信号转导与内源性过氧化物酶体增殖物激活受体γ（PPARγ）表达在心脏成纤维细胞和压力负荷心脏中存在功能性相互作用的假设。我们观察到，响应于由横向主动脉缩窄诱导的压力超负荷，野生型小鼠的左心室PPARγ蛋白水平降低，但在具有人TGF-β II型受体显性负突变（DnTGFβRII）的可诱导过表达的小鼠中增加，其中TGF-β信号传导被阻断。在分离的小鼠心脏成纤维细胞中，我们证明TGF-β1处理降低了稳态PPARγ mRNA（−34%）和蛋白（−52%）水平，以及PPARγ转录活性（−53%）。染色质免疫沉淀分析显示，TGF-β1处理增加了Smad 2/3、Smad 4和组蛋白去乙酰化酶1的结合，降低了乙酰化组蛋白3与心肌成纤维细胞中PPARγ启动子的结合。在离体心脏成纤维细胞中，药理学激活和过表达的PPARγ均显著抑制TGF-β1诱导的细胞外基质分子表达，而用PPARγ激动剂罗格列酮治疗抑制，用PPARγ拮抗剂T0070907治疗加重了野生型小鼠体内慢性压力超负荷诱导的心脏纤维化和重塑。这些数据为TGF-β1通过转录机制直接抑制心脏成纤维细胞中的PPARγ表达提供了强有力的证据，并表明TGF-β下调内源性PPARγ表达可能参与了压力超负荷诱导的心脏纤维化。
Pharmacological activation of peroxisome proliferator-activated receptor gamma (PPARγ) has been shown to attenuate pressure overload-induced cardiac fibrosis, suggesting that PPARγ has an antifibrotic effect. This study tested the hypothesis that there is a functional interaction between transforming growth factor-β (TGF-β) signaling and endogenous PPARγ expression in cardiac fibroblasts and pressure overloaded heart. We observed that, in response to pressure overload induced by transverse aortic constriction, left-ventricular PPARγ protein levels were decreased in wild-type mice, but increased in mice with an inducible overexpression of dominant negative mutation of the human TGF-β type II receptor (DnTGFβRII), in which TGF-β signaling is blocked. In isolated mouse cardiac fibroblasts, we demonstrated that TGF-β1 treatment decreased steady state PPARγ mRNA (−34%) and protein (−52%) levels, as well as PPARγ transcriptional activity (−53%). Chromatin immunoprecipitation analysis showed that TGF-β1 treatment increased binding of Smad2/3, Smad4 and histone deacetylase 1, and decreased binding of acetylated histone 3 to the PPARγ promoter in cardiac fibroblasts. Both pharmacological activation and overexpression of PPARγ significantly inhibited TGF-β1-induced extracellular matrix molecule expression in isolated cardiac fibroblasts, whereas treatment with the PPARγ agonist rosiglitazone inhibited, and treatment with the PPARγ antagonist T0070907 exacerbated chronic pressure overload-induced cardiac fibrosis and remodeling in wild-type mice in vivo. These data provide strong evidence that TGF-β1 directly suppresses PPARγ expression in cardiac fibroblasts via a transcriptional mechanism and suggest that the down-regulation of endogenous PPARγ expression by TGF-β may be involved in pressure overload-induced cardiac fibrosis.