Vascular Biology and Hypertension Program, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
J Hypertens. 2011 Sep;29(9):1810-9. doi: 10.1097/HJH.0b013e32834a4d03.
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.
过氧化物酶体增殖物激活受体γ（PPARγ）的药理学激活已被证明可减轻压力超负荷引起的心肌纤维化，表明 PPARγ 具有抗纤维化作用。本研究检验了这样一个假设，即在心肌成纤维细胞和压力超负荷心脏中，转化生长因子-β（TGF-β）信号与内源性 PPARγ 表达之间存在功能相互作用。
我们观察到，在由主动脉缩窄引起的压力超负荷反应中，野生型小鼠的左心室 PPARγ 蛋白水平降低，但在 TGF-β 型 II 受体（DnTGFβRII）的诱导过表达的小鼠中增加，其中 TGF-β 信号被阻断。在分离的小鼠心肌成纤维细胞中，我们证明 TGF-β1 处理降低了 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 Smad2/3、Smad4 和组蛋白去乙酰化酶 1 的结合，并减少了乙酰化组蛋白 3 与 PPARγ 启动子的结合。PPARγ 的药理学激活和过表达均可显著抑制分离的心肌成纤维细胞中 TGF-β1 诱导的细胞外基质分子表达，而 PPARγ 激动剂罗格列酮的处理抑制了，而 PPARγ 拮抗剂 T0070907 的处理则加剧了体内野生型小鼠慢性压力超负荷诱导的心肌纤维化和重塑。
这些数据提供了有力的证据，表明 TGF-β1 通过转录机制直接抑制心肌成纤维细胞中的 PPARγ 表达，并表明 TGF-β 下调内源性 PPARγ 表达可能参与压力超负荷诱导的心肌纤维化。
