title: An endothelial apelin-FGF link mediated by miR-424 and miR-503 is disrupted in pulmonary arterial hypertension.
abstract: Pulmonary arterial hypertension (PAH) is characterized by vascular remodeling associated with obliteration of pulmonary arterioles and formation of plexiform lesions composed of hyperproliferative endothelial and vascular smooth-muscle cells. Here we describe a microRNA (miRNA)-dependent association between apelin (APLN) and fibroblast growth factor 2 (FGF2) signaling in pulmonary artery endothelial cells (PAECs). APLN deficiency in these cells led to increased expression of FGF2 and its receptor FGFR1 as a consequence of decreased expression of miR-424 and miR-503, which directly target FGF2 and FGFR1. miR-424 and miR-503 were downregulated in PAH, exerted antiproliferative effects in PAECs and inhibited the capacity of PAEC-conditioned medium to induce the proliferation of pulmonary artery smooth-muscle cells. Reconstitution of miR-424 and miR-503 in vivo ameliorated pulmonary hypertension in experimental models. These studies identify an APLN-dependent miRNA-FGF signaling axis needed for the maintenance of pulmonary vascular homeostasis.
authors.affiliation: Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Jongmin
authors.initials: J
authors.lastname: Kim
authors.forename: Yujung
authors.initials: Y
authors.lastname: Kang
authors.forename: Yoko
authors.initials: Y
authors.lastname: Kojima
authors.forename: Janet K
authors.initials: JK
authors.lastname: Lighthouse
authors.forename: Xiaoyue
authors.initials: X
authors.lastname: Hu
authors.forename: Micheala A
authors.initials: MA
authors.lastname: Aldred
authors.forename: Danielle L
authors.initials: DL
authors.lastname: McLean
authors.forename: Hyekyung
authors.initials: H
authors.lastname: Park
authors.forename: Suzy A
authors.initials: SA
authors.lastname: Comhair
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Greif
authors.forename: Serpil C
authors.initials: SC
authors.lastname: Erzurum
authors.forename: Hyung J
authors.initials: HJ
authors.lastname: Chun
mesh_terms: D000818:Animals; D000073861:Apelin; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D015536:Down-Regulation; D042783:Endothelial Cells / Q000378:metabolism; D065627:Familial Primary Pulmonary Hypertension; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D034622:RNA Interference; D034741:RNA, Small Interfering; D051381:Rats; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000096:biosynthesis; D015398:Signal Transduction; D014652:Vascular Diseases / Q000378:metabolism
chemical_list: C115436:APLN protein, human; D000073861:Apelin; D017077:Culture Media, Conditioned; D036341:Intercellular Signaling Peptides and Proteins; C554214:MIRN424 microrna, human; C545473:MIRN503 microRNA, human; D035683:MicroRNAs; D034741:RNA, Small Interfering; D016222:Fibroblast Growth Factor 2; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1