An antiproliferative BMP-2/PPARγ/apoE axis in human and murine SMCs and its role in pulmonary hypertension
An antiproliferative BMP-2/PPARγ/apoE axis in human and murine SMCs and its role in pulmonary hypertension
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DOI：
10.1172/jci32503
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发表时间：
2008-05-01
影响因子：
15.9
通讯作者：
Rabinovitch, Marlene
中科院分区：
文献类型：
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作者：
Hansmann, Georg;de Jesus Perez, Vinicio A.;Rabinovitch, Marlene
骨形态发生蛋白受体 II (BMP-RII) 的功能丧失突变与肺动脉高压 (PAH) 有关； BMP-RII 的配体 BMP-2 是 SMC 生长的负调节因子。在此，我们报告了 PPAR gamma 与其 BMP-2 信号下游转录靶标 apoE 之间的相互作用。 BMP-2/BMP-RII 信号通过减少核磷酸化 ERK 并诱导与 Smad1/5/8 磷酸化无关的 PPAR gamma DNA 结合，阻止 PDGF-BB 诱导的人和小鼠肺动脉 SMC (PASMC) 增殖。 BMP-2 和 PPAR γ 激动剂均刺激 SMC 产生和分泌 apoE。使用多种方法，包括人 PASMC 中的短发夹 RNAi、PAH 患者来源的 BMP-RII 突变型 PASMC、PPAR γ 拮抗剂以及从 PPAR γ 和 apoE 缺陷小鼠中分离的 PASMC，我们证明了 BMP-2 的抗增殖作用是 BMP-RII、PPAR γ 和 apoE 依赖性的。此外，我们创建了在 SMC 中定向删除 PPAR γ 的小鼠，结果表明它们会自发地患上 PAH，表现为右心室收缩压升高、右心室肥大和远端肺动脉肌化增加。因此，PPAR γ 介导的事件可以预防 PAH，而 PPAR γ 激动剂可以逆转有或没有 BMP-RII 功能障碍的患者的 PAH。
Loss-of-function mutations in bone morphogenetic protein receptor II (BMP-RII) are linked to pulmonary arterial hypertension (PAH); the ligand for BMP-RII, BMP-2, is a negative regulator of SMC growth. Here, we report an interplay between PPAR gamma and its transcriptional target apoE downstream of BMP-2 signaling. BMP-2/BMP-RII signaling prevented PDGF-BB-induced proliferation of human and murine pulmonary artery SMCs (PASMCs) by decreasing nuclear phospho-ERK and inducing DNA binding of PPAR gamma that is independent of Smad1/5/8 phosphorylation. Both BMP-2 and a PPAR gamma agonist stimulated production and secretion of apoE by SMCs. Using a variety of methods, including short hairpin RNAi in human PASMCs, PAH patient-derived BMP-RII mutant PASMCs, a PPAR gamma antagonist, and PASMCs isolated from PPAR gamma- and apoE-deficient mice, we demonstrated that the antiproliferative effect of BMP-2 was BMP-RII, PPAR gamma, and apoE dependent. Furthermore, we created mice with targeted deletion of PPAR gamma in SMCs and showed that they spontaneously developed PAH, as indicated by elevated RV systolic pressure, RV hypertrophy, and increased muscularization of the distal pulmonary arteries. Thus, PPAR gamma-mediated events could protect against PAH, and PPAR gamma agonists may reverse PAH in patients with or without BMP-RII dysfunction.