PPARγ Ligands Attenuate Hypoxia-Induced Proliferation in Human Pulmonary Artery Smooth Muscle Cells through Modulation of MicroRNA-21

作者: David E. Green , Tamara C. Murphy , Bum-Yong Kang , Charles D. Searles , C. Michael Hart

DOI: 10.1371/JOURNAL.PONE.0133391

关键词:

摘要: 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 molecular targets. MicroRNA (miR)-21 has emerged as an important non-coding RNA that contributes to by enhancing vascular proliferation, however little known about available modulate its expression. We previously demonstrated peroxisome proliferator-activated receptor gamma (PPARγ) agonists attenuated hypoxia-induced HPASMC remodeling through pleiotropic actions multiple targets, including transforming growth factor (TGF)-β1 phosphatase tensin homolog deleted chromosome 10 (PTEN). PTEN validated target miR-21. therefore hypothesized antiproliferative effects conferred PPARγ activation are mediated inhibition miR-21 Human PASMC monolayers were exposed hypoxia then treated with agonist, rosiglitazone (RSG,10 μM), or in parallel, C57Bl/6J mice RSG. RSG hypoxic increases expression vitro vivo abrogated reductions Antiproliferative lost following siRNA-mediated depletion. Furthermore, mimic decreased stimulated whereas increased Collectively, these results demonstrate ligands regulate proliferative responses preventing PTEN. These findings further clarify mechanisms support targeting attenuate pathogenic derangements PH.

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