MicroRNA-21 plays a role in hypoxia-mediated pulmonary artery smooth muscle cell proliferation and migration

Sarkar J, Gou D, Turaka P, Viktorova E, Ramchandran R, Raj JU. MicroRNA-21 plays a role in hypoxia-mediated pulmonary artery smooth muscle cell proliferation and migration. Am J Physiol Lung Cell Mol Physiol 299: L861-L871, 2010. First published August 6, 2010; doi:10.1152/ajplung.00201.2010.-Hypoxia stimulates pulmonary artery smooth muscle cell (PASMC) proliferation. Recent studies have implicated an important role for microRNAs (miRNAs) in hypoxia-mediated responses in various cellular processes, including cell proliferation. In this study, we investigated the role of microRNA-21 (miR-21) in hypoxia-induced PASMC proliferation and migration. We first demonstrated that miR-21 expression increased by similar to 3-fold in human PASMC after 6 h of hypoxia (3% O(2)) and remained high (similar to 2-fold) after 24 h of hypoxia. Knockdown of miR-21 with anti-miR-21 inhibitors significantly reduced hypoxia-induced cell proliferation, whereas miR-21 overexpression in normoxia enhanced cell proliferation. We also found that miR-21 is essential for hypoxia-induced cell migration. Protein expression of miR-21 target genes, specifically programmed cell death protein 4 (PDCD4), Sprouty 2 (SPRY2), and peroxisome proliferator-activated receptor-alpha (PPAR alpha), was decreased in hypoxia and in PASMC overexpressing miR-21 in normoxia and increased in hypoxic cells in which miR-21 was knocked down. In addition, PPAR alpha 3'-untranslated region (UTR) luciferase-based reporter gene assays demonstrated that PPAR alpha is a direct target of miR-21. Taken together, our findings indicate that miR-21 plays a significant role in hypoxia-induced pulmonary vascular smooth muscle cell proliferation and migration by regulating multiple gene targets.