PPARγ Ligands Attenuate Hypoxia-Induced Proliferation in Human Pulmonary Artery Smooth Muscle Cells through Modulation of MicroRNA-21.
PPARγ Ligands Attenuate Hypoxia-Induced Proliferation in Human Pulmonary Artery Smooth Muscle Cells through Modulation of MicroRNA-21.
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DOI：
10.1371/journal.pone.0133391
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Hart CM
中科院分区：
文献类型：
--
作者：
Green DE;Murphy TC;Kang BY;Searles CD;Hart CM
肺动脉高压（PH）是一种进行性、致命性疾病，其发病机制与肺动脉平滑肌细胞（PASMC）增生有关。尽管现代PH疗法显著提高了生存率，但持续的进展取决于新疗法和分子靶点的发现。MicroRNA (miR)-21已经成为一种重要的非编码RNA，通过促进血管细胞增殖来促进PH的发病机制，然而对于调节其表达的可用治疗方法知之甚少。我们之前证明过氧化物酶体增殖物激活受体γ (PPARγ)激动剂通过对多个靶点的多效作用，包括转化生长因子(TGF)-β1和10号染色体上缺失的磷酸酶和紧张素同源物（PTEN），减弱缺氧诱导的HPASMC增殖、血管重塑和PH。PTEN是miR-21的有效靶标。因此，我们假设PPARγ激活的抗增殖作用是通过抑制缺氧诱导的miR-21表达介导的。将人PASMC单层暴露在缺氧条件下，然后用PPARγ激动剂罗格列酮（RSG,10 μM）处理，或将C57Bl/6J小鼠暴露在缺氧条件下，然后用RSG处理。在体外和体内，RSG减弱了低氧条件下miR-21表达的增加，并消除了PTEN和PASMC增殖的减少。在sirna介导的PTEN缺失后，RSG的抗增殖作用丧失。此外，miR-21模拟降低PTEN并刺激PASMC增殖，而miR-21抑制增加PTEN并减弱缺氧诱导的HPASMC增殖。总的来说，这些结果表明PPARγ配体通过阻止miR-21的缺氧增加和PTEN的减少来调节对缺氧的增殖反应。这些发现进一步阐明了支持靶向PPARγ减轻PH致病性紊乱的分子机制。
Pulmonary hypertension (PH) is a progressive and often fatal disorder whose pathogenesis involves pulmonary artery smooth muscle cell (PASMC) proliferation. Although modern PH therapies have significantly improved survival, continued progress rests on the discovery of novel therapies and molecular targets. MicroRNA (miR)-21 has emerged as an important non-coding RNA that contributes to PH pathogenesis by enhancing vascular cell proliferation, however little is known about available therapies that modulate its expression. We previously demonstrated that peroxisome proliferator-activated receptor gamma (PPARγ) agonists attenuated hypoxia-induced HPASMC proliferation, vascular remodeling and PH through pleiotropic actions on multiple targets, including transforming growth factor (TGF)-β1 and phosphatase and tensin homolog deleted on chromosome 10 (PTEN). PTEN is a validated target of miR-21. We therefore hypothesized that antiproliferative effects conferred by PPARγ activation are mediated through inhibition of hypoxia-induced miR-21 expression. Human PASMC monolayers were exposed to hypoxia then treated with the PPARγ agonist, rosiglitazone (RSG,10 μM), or in parallel, C57Bl/6J mice were exposed to hypoxia then treated with RSG. RSG attenuated hypoxic increases in miR-21 expression in vitro and in vivo and abrogated reductions in PTEN and PASMC proliferation. Antiproliferative effects of RSG were lost following siRNA-mediated PTEN depletion. Furthermore, miR-21 mimic decreased PTEN and stimulated PASMC proliferation, whereas miR-21 inhibition increased PTEN and attenuated hypoxia-induced HPASMC proliferation. Collectively, these results demonstrate that PPARγ ligands regulate proliferative responses to hypoxia by preventing hypoxic increases in miR-21 and reductions in PTEN. These findings further clarify molecular mechanisms that support targeting PPARγ to attenuate pathogenic derangements in PH.