Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
Division of Allergy and Clinical Immunology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21224.
Mol Biol Cell. 2018 Feb 1;29(3):356-362. doi: 10.1091/mbc.E17-03-0141. Epub 2017 Dec 6.
Loss of peroxisome proliferator-activated receptor γ (PPARγ) has been found to contribute to pulmonary artery smooth muscle cell (PASMC) proliferation and pulmonary arterial remodeling therefore the development of pulmonary hypertension (PH). Yet, the molecular mechanisms underlying PPARγ reduction in PASMC remain poorly understood. Here, we demonstrated that leptin dose- and time-dependently inducued PPARγ down-regulation and proliferation of primary cultured rat PASMC, this was accompanied with the activation of extracellular regulated kinase1/2 (ERK1/2) signaling pathway and subsequent induction of early growth response-1 (Egr-1) expression. The presence of MEK inhibitors U0126 or PD98059, or prior silencing Egr-1 with small interfering RNA suppressed leptin-induced PPARγ reduction. In addition, activation of PPARγ by pioglitazone or targeting ERK1/2/Egr-1 suppressed leptin-induced PASMC proliferation. Taken together, our study indicates that ERK1/2 signaling pathway-mediated leptin-induced PPARγ reduction and PASMC proliferation through up-regulation of Egr-1 and suggests that targeting leptin/ERK1/2/Egr-1 pathway might have potential value in ameliorating vascular remodeling and benefit PH.
过氧化物酶体增殖物激活受体 γ（PPARγ）的缺失已被发现有助于肺动脉平滑肌细胞（PASMC）的增殖和肺血管重塑，从而导致肺动脉高压（PH）的发展。然而，PASMC 中 PPARγ减少的分子机制仍知之甚少。在这里，我们证明瘦素以剂量和时间依赖的方式诱导原代培养的大鼠 PASMC 中 PPARγ 的下调和增殖，这伴随着细胞外调节激酶 1/2（ERK1/2）信号通路的激活和随后早期生长反应-1（Egr-1）表达的诱导。用 MEK 抑制剂 U0126 或 PD98059 预处理或用小干扰 RNA 预先沉默 Egr-1，可抑制瘦素诱导的 PPARγ减少。此外，用吡格列酮激活 PPARγ或针对 ERK1/2/Egr-1 可抑制瘦素诱导的 PASMC 增殖。总之，我们的研究表明，ERK1/2 信号通路介导的瘦素诱导的 PPARγ减少和 PASMC 增殖是通过上调 Egr-1 实现的，并表明靶向瘦素/ERK1/2/Egr-1 途径可能在改善血管重塑和有益于 PH 方面具有潜在价值。
