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

• Type of Material: Article
• Authors: David Green, Emory University; Tamara C. Murphy, Emory University; Bum-Yong Kang, Emory University; Charles Searles Jr, Emory University; Charles Hart, Emory University
• Language: English
• Date: 2015
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: This is an open access article, free of all copyright
• License: Creative Commons Creative Commons CC0 1.0 Universal
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pone.0133391
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 10
• Issue: 7
• Start Page: e0133391
• End Page: e0133391
• Grant/Funding Information: This work was supported by the Veterans Affairs Career Development -02 (1 IK2 BX001707-01A1)- http://www.research.va.gov/funding/- to DG, the National Institutes of Health R01 (HL102167) http://www.grants.nih.gov/grants/funding/r01.htm- to CH, and the Veterans Affairs Merit Review Award (101BX001910-01) http://www.research.va.gov/funding/ to CH.
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, General

Abstract

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.