Hypoxia mediates mutual repression between microRNA-27a and PPARγ in the pulmonary vasculature.
Hypoxia mediates mutual repression between microRNA-27a and PPARγ in the pulmonary vasculature.
复制标题
DOI：
10.1371/journal.pone.0079503
复制
发表时间：
2013
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：
Kang BY;Park KK;Green DE;Bijli KM;Searles CD;Sutliff RL;Hart CM
肺动脉高压（PH）是一种严重的疾病，可导致显着的发病率和死亡率。 PH 的发病机制涉及多种途径的复杂紊乱，包括过氧化物酶体增殖物激活受体 γ (PPARγ) 的减少。缺氧是一种常见的 PH 刺激，在实验模型中会降低 PPARγ。相反，激活 PPARγ 会减弱缺氧诱导的 PH 和内皮素 1 (ET-1) 的表达。为了进一步探索缺氧诱导的 PH 和 PPARγ 减少的机制，我们检查了缺氧对选定的 microRNA（miRNA 或 miR）水平的影响，这些 microRNA 水平可能会减少 PPARγ 表达，从而导致 ET-1 表达和 PH 增加。我们的结果表明，暴露于缺氧（10% O2）3周会增加C57BL/6小鼠肺部的miR-27a和ET-1水平，并降低PPARγ水平。在用 PPARγ 配体罗格列酮（RSG，10 mg/kg/d）治疗的小鼠中，通过在暴露的最后 10 天进行管饲，缺氧诱导的 miR-27a 增加被减弱。在平行研究中，人肺动脉内皮细胞 (HPAEC) 暴露于对照 (21% O2) 或低氧 (1% O2) 条件下 72 小时。缺氧增加 HPAEC 增殖、miR-27a 和 ET-1 表达，并减少 PPARγ 表达。在缺氧暴露的最后 24 小时内使用 RSG (10 µM) 处理可减弱这些变化。 miR-27a 的过度表达或 PPARγ 敲低会增加 HPAEC 增殖和 ET-1 表达，并降低 PPARγ 水平，而这些效应可通过抑制 miR-27a 来逆转。此外，与同窝对照小鼠的肺相比，内皮靶向 PPARγ 敲除 (ePPARγ KO) 小鼠的肺中 miR-27a 水平上调。 SP1 或 EGR1 的敲低足以显着减弱 HPAEC 中 miR-27a 的表达。总的来说，这些研究提供了新的证据，表明 miR-27a 和 PPARγ 在缺氧肺血管系统中介导相互抑制作用，并且靶向 PPARγ 可能代表了一种新的 PH 治疗方法，可减弱刺激肺血管细胞增殖的增殖介质。
Pulmonary hypertension (PH) is a serious disorder that causes significant morbidity and mortality. The pathogenesis of PH involves complex derangements in multiple pathways including reductions in peroxisome proliferator-activated receptor gamma (PPARγ). Hypoxia, a common PH stimulus, reduces PPARγ in experimental models. In contrast, activating PPARγ attenuates hypoxia-induced PH and endothelin 1 (ET-1) expression. To further explore mechanisms of hypoxia-induced PH and reductions in PPARγ, we examined the effects of hypoxia on selected microRNA (miRNA or miR) levels that might reduce PPARγ expression leading to increased ET-1 expression and PH. Our results demonstrate that exposure to hypoxia (10% O2) for 3-weeks increased levels of miR-27a and ET-1 in the lungs of C57BL/6 mice and reduced PPARγ levels. Hypoxia-induced increases in miR-27a were attenuated in mice treated with the PPARγ ligand, rosiglitazone (RSG, 10 mg/kg/d) by gavage for the final 10 d of exposure. In parallel studies, human pulmonary artery endothelial cells (HPAECs) were exposed to control (21% O2) or hypoxic (1% O2) conditions for 72 h. Hypoxia increased HPAEC proliferation, miR-27a and ET-1 expression, and reduced PPARγ expression. These alterations were attenuated by treatment with RSG (10 µM) during the last 24 h of hypoxia exposure. Overexpression of miR-27a or PPARγ knockdown increased HPAEC proliferation and ET-1 expression and decreased PPARγ levels, whereas these effects were reversed by miR-27a inhibition. Further, compared to lungs from littermate control mice, miR-27a levels were upregulated in lungs from endothelial-targeted PPARγ knockout (ePPARγ KO) mice. Knockdown of either SP1 or EGR1 was sufficient to significantly attenuate miR-27a expression in HPAECs. Collectively, these studies provide novel evidence that miR-27a and PPARγ mediate mutually repressive actions in hypoxic pulmonary vasculature and that targeting PPARγ may represent a novel therapeutic approach in PH to attenuate proliferative mediators that stimulate proliferation of pulmonary vascular cells.
登录
查看更多内容
影响因子：
37.3
作者：
Chhabra R;Dubey R;Saini N
通讯作者：
Saini N
影响因子：
2.6
作者：
Joshi SR;McLendon JM;Comer BS;Gerthoffer WT
通讯作者：
Gerthoffer WT
DOI：
10.1152/ajplung.00258.2006
发表时间：
2007-04-01
影响因子：
4.9
作者：
Crossno, Joseph T.;Garat, Chrystelle V.;Klemm, Dwight J.
通讯作者：
Klemm, Dwight J.
影响因子：
4.8
作者：
Jennewein, Carla;von Knethen, Andreas;Bruene, Bernhard
通讯作者：
Bruene, Bernhard
影响因子：
158.5
作者：
GIAID, A;YANAGISAWA, M;STEWART, DJ
通讯作者：
STEWART, DJ