title: Downregulation of MicroRNA-126 Contributes to the Failing Right Ventricle in Pulmonary Arterial Hypertension.
abstract: BACKGROUND
  Right ventricular (RV) failure is the most important factor of both morbidity and mortality in pulmonary arterial hypertension (PAH). However, the underlying mechanisms resulting in the failed RV in PAH remain unknown. There is growing evidence that angiogenesis and microRNAs are involved in PAH-associated RV failure. We hypothesized that microRNA-126 (miR-126) downregulation decreases microvessel density and promotes the transition from a compensated to a decompensated RV in PAH.
  
  
  RESULTS
  We studied RV free wall tissues from humans with normal RV (n=17), those with compensated RV hypertrophy (n=8), and patients with PAH with decompensated RV failure (n=14). Compared with RV tissues from patients with compensated RV hypertrophy, patients with decompensated RV failure had decreased miR-126 expression (quantitative reverse transcription-polymerase chain reaction; P<0.01) and capillary density (CD31(+) immunofluorescence; P<0.001), whereas left ventricular tissues were not affected. miR-126 downregulation was associated with increased Sprouty-related EVH1 domain-containing protein 1 (SPRED-1), leading to decreased activation of RAF (phosphorylated RAF/RAF) and mitogen-activated protein kinase (MAPK); (phosphorylated MAPK/MAPK), thus inhibiting the vascular endothelial growth factor pathway. In vitro, Matrigel assay showed that miR-126 upregulation increased angiogenesis of primary cultured endothelial cells from patients with decompensated RV failure. Furthermore, in vivo miR-126 upregulation (mimic intravenous injection) improved cardiac vascular density and function of monocrotaline-induced PAH animals.
  
  
  CONCLUSIONS
  RV failure in PAH is associated with a specific molecular signature within the RV, contributing to a decrease in RV vascular density and promoting the progression to RV failure. More importantly, miR-126 upregulation in the RV improves microvessel density and RV function in experimental PAH.
authors.affiliation: From Pulmonary Hypertension Research Group of the Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center, Laval University, Quebec City, QC, Canada (F.P., G.R., A.D., C.T., S.B.-B., E.T., V.N., R. Paradis, C.G., R.W., I.J., A.C.L., J.P., E.C., P.J., P.P., S.P., S.B.); and Vascular Biology Research Group, Department of Medicine, University of Alberta, Edmonton, AB, Canada (R. Paulin, E.D.M.).
authors.forename: François
authors.initials: F
authors.lastname: Potus
authors.affiliation: From Pulmonary Hypertension Research Group of the Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center, Laval University, Quebec City, QC, Canada (F.P., G.R., A.D., C.T., S.B.-B., E.T., V.N., R. Paradis, C.G., R.W., I.J., A.C.L., J.P., E.C., P.J., P.P., S.P., S.B.); and Vascular Biology Research Group, Department of Medicine, University of Alberta, Edmonton, AB, Canada (R. Paulin, E.D.M.).
authors.forename: Grégoire
authors.initials: G
authors.lastname: Ruffenach
authors.affiliation: From Pulmonary Hypertension Research Group of the Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center, Laval University, Quebec City, QC, Canada (F.P., G.R., A.D., C.T., S.B.-B., E.T., V.N., R. Paradis, C.G., R.W., I.J., A.C.L., J.P., E.C., P.J., P.P., S.P., S.B.); and Vascular Biology Research Group, Department of Medicine, University of Alberta, Edmonton, AB, Canada (R. Paulin, E.D.M.).
authors.forename: Abdellaziz
authors.initials: A
authors.lastname: Dahou
authors.affiliation: From Pulmonary Hypertension Research Group of the Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center, Laval University, Quebec City, QC, Canada (F.P., G.R., A.D., C.T., S.B.-B., E.T., V.N., R. Paradis, C.G., R.W., I.J., A.C.L., J.P., E.C., P.J., P.P., S.P., S.B.); and Vascular Biology Research Group, Department of Medicine, University of Alberta, Edmonton, AB, Canada (R. Paulin, E.D.M.).
authors.forename: Christophe
authors.initials: C
authors.lastname: Thebault
authors.affiliation: From Pulmonary Hypertension Research Group of the Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center, Laval University, Quebec City, QC, Canada (F.P., G.R., A.D., C.T., S.B.-B., E.T., V.N., R. Paradis, C.G., R.W., I.J., A.C.L., J.P., E.C., P.J., P.P., S.P., S.B.); and Vascular Biology Research Group, Department of Medicine, University of Alberta, Edmonton, AB, Canada (R. Paulin, E.D.M.).
authors.forename: Sandra
authors.initials: S
authors.lastname: Breuils-Bonnet
authors.affiliation: From Pulmonary Hypertension Research Group of the Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center, Laval University, Quebec City, QC, Canada (F.P., G.R., A.D., C.T., S.B.-B., E.T., V.N., R. Paradis, C.G., R.W., I.J., A.C.L., J.P., E.C., P.J., P.P., S.P., S.B.); and Vascular Biology Research Group, Department of Medicine, University of Alberta, Edmonton, AB, Canada (R. Paulin, E.D.M.).
authors.forename: Ève
authors.initials: È
authors.lastname: Tremblay
authors.affiliation: From Pulmonary Hypertension Research Group of the Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center, Laval University, Quebec City, QC, Canada (F.P., G.R., A.D., C.T., S.B.-B., E.T., V.N., R. Paradis, C.G., R.W., I.J., A.C.L., J.P., E.C., P.J., P.P., S.P., S.B.); and Vascular Biology Research Group, Department of Medicine, University of Alberta, Edmonton, AB, Canada (R. Paulin, E.D.M.).
authors.forename: Valérie
authors.initials: V
authors.lastname: Nadeau
authors.affiliation: From Pulmonary Hypertension Research Group of the Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center, Laval University, Quebec City, QC, Canada (F.P., G.R., A.D., C.T., S.B.-B., E.T., V.N., R. Paradis, C.G., R.W., I.J., A.C.L., J.P., E.C., P.J., P.P., S.P., S.B.); and Vascular Biology Research Group, Department of Medicine, University of Alberta, Edmonton, AB, Canada (R. Paulin, E.D.M.).
authors.forename: Renée
authors.initials: R
authors.lastname: Paradis
authors.affiliation: From Pulmonary Hypertension Research Group of the Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center, Laval University, Quebec City, QC, Canada (F.P., G.R., A.D., C.T., S.B.-B., E.T., V.N., R. Paradis, C.G., R.W., I.J., A.C.L., J.P., E.C., P.J., P.P., S.P., S.B.); and Vascular Biology Research Group, Department of Medicine, University of Alberta, Edmonton, AB, Canada (R. Paulin, E.D.M.).
authors.forename: Colin
authors.initials: C
authors.lastname: Graydon
authors.affiliation: From Pulmonary Hypertension Research Group of the Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center, Laval University, Quebec City, QC, Canada (F.P., G.R., A.D., C.T., S.B.-B., E.T., V.N., R. Paradis, C.G., R.W., I.J., A.C.L., J.P., E.C., P.J., P.P., S.P., S.B.); and Vascular Biology Research Group, Department of Medicine, University of Alberta, Edmonton, AB, Canada (R. Paulin, E.D.M.).
authors.forename: Ryan
authors.initials: R
authors.lastname: Wong
authors.affiliation: From Pulmonary Hypertension Research Group of the Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center, Laval University, Quebec City, QC, Canada (F.P., G.R., A.D., C.T., S.B.-B., E.T., V.N., R. Paradis, C.G., R.W., I.J., A.C.L., J.P., E.C., P.J., P.P., S.P., S.B.); and Vascular Biology Research Group, Department of Medicine, University of Alberta, Edmonton, AB, Canada (R. Paulin, E.D.M.).
authors.forename: Ian
authors.initials: I
authors.lastname: Johnson
authors.affiliation: From Pulmonary Hypertension Research Group of the Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center, Laval University, Quebec City, QC, Canada (F.P., G.R., A.D., C.T., S.B.-B., E.T., V.N., R. Paradis, C.G., R.W., I.J., A.C.L., J.P., E.C., P.J., P.P., S.P., S.B.); and Vascular Biology Research Group, Department of Medicine, University of Alberta, Edmonton, AB, Canada (R. Paulin, E.D.M.).
authors.forename: Roxane
authors.initials: R
authors.lastname: Paulin
authors.affiliation: From Pulmonary Hypertension Research Group of the Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center, Laval University, Quebec City, QC, Canada (F.P., G.R., A.D., C.T., S.B.-B., E.T., V.N., R. Paradis, C.G., R.W., I.J., A.C.L., J.P., E.C., P.J., P.P., S.P., S.B.); and Vascular Biology Research Group, Department of Medicine, University of Alberta, Edmonton, AB, Canada (R. Paulin, E.D.M.).
authors.forename: Annie C
authors.initials: AC
authors.lastname: Lajoie
authors.affiliation: From Pulmonary Hypertension Research Group of the Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center, Laval University, Quebec City, QC, Canada (F.P., G.R., A.D., C.T., S.B.-B., E.T., V.N., R. Paradis, C.G., R.W., I.J., A.C.L., J.P., E.C., P.J., P.P., S.P., S.B.); and Vascular Biology Research Group, Department of Medicine, University of Alberta, Edmonton, AB, Canada (R. Paulin, E.D.M.).
authors.forename: Jean
authors.initials: J
authors.lastname: Perron
authors.affiliation: From Pulmonary Hypertension Research Group of the Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center, Laval University, Quebec City, QC, Canada (F.P., G.R., A.D., C.T., S.B.-B., E.T., V.N., R. Paradis, C.G., R.W., I.J., A.C.L., J.P., E.C., P.J., P.P., S.P., S.B.); and Vascular Biology Research Group, Department of Medicine, University of Alberta, Edmonton, AB, Canada (R. Paulin, E.D.M.).
authors.forename: Eric
authors.initials: E
authors.lastname: Charbonneau
authors.affiliation: From Pulmonary Hypertension Research Group of the Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center, Laval University, Quebec City, QC, Canada (F.P., G.R., A.D., C.T., S.B.-B., E.T., V.N., R. Paradis, C.G., R.W., I.J., A.C.L., J.P., E.C., P.J., P.P., S.P., S.B.); and Vascular Biology Research Group, Department of Medicine, University of Alberta, Edmonton, AB, Canada (R. Paulin, E.D.M.).
authors.forename: Philippe
authors.initials: P
authors.lastname: Joubert
authors.affiliation: From Pulmonary Hypertension Research Group of the Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center, Laval University, Quebec City, QC, Canada (F.P., G.R., A.D., C.T., S.B.-B., E.T., V.N., R. Paradis, C.G., R.W., I.J., A.C.L., J.P., E.C., P.J., P.P., S.P., S.B.); and Vascular Biology Research Group, Department of Medicine, University of Alberta, Edmonton, AB, Canada (R. Paulin, E.D.M.).
authors.forename: Philippe
authors.initials: P
authors.lastname: Pibarot
authors.affiliation: From Pulmonary Hypertension Research Group of the Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center, Laval University, Quebec City, QC, Canada (F.P., G.R., A.D., C.T., S.B.-B., E.T., V.N., R. Paradis, C.G., R.W., I.J., A.C.L., J.P., E.C., P.J., P.P., S.P., S.B.); and Vascular Biology Research Group, Department of Medicine, University of Alberta, Edmonton, AB, Canada (R. Paulin, E.D.M.).
authors.forename: Evangelos D
authors.initials: ED
authors.lastname: Michelakis
authors.affiliation: From Pulmonary Hypertension Research Group of the Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center, Laval University, Quebec City, QC, Canada (F.P., G.R., A.D., C.T., S.B.-B., E.T., V.N., R. Paradis, C.G., R.W., I.J., A.C.L., J.P., E.C., P.J., P.P., S.P., S.B.); and Vascular Biology Research Group, Department of Medicine, University of Alberta, Edmonton, AB, Canada (R. Paulin, E.D.M.). sebastien.bonnet@criucpq.ulaval.ca Steeve.Provencher@criucpq.ulaval.ca.
authors.forename: Steeve
authors.initials: S
authors.lastname: Provencher
authors.affiliation: From Pulmonary Hypertension Research Group of the Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center, Laval University, Quebec City, QC, Canada (F.P., G.R., A.D., C.T., S.B.-B., E.T., V.N., R. Paradis, C.G., R.W., I.J., A.C.L., J.P., E.C., P.J., P.P., S.P., S.B.); and Vascular Biology Research Group, Department of Medicine, University of Alberta, Edmonton, AB, Canada (R. Paulin, E.D.M.). sebastien.bonnet@criucpq.ulaval.ca Steeve.Provencher@criucpq.ulaval.ca.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Bonnet
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation / Q000502:physiology*; D005260:Female; D006333:Heart Failure / Q000175:diagnosis / Q000378:metabolism*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000175:diagnosis / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D051381:Rats; D017207:Rats, Sprague-Dawley; D018497:Ventricular Dysfunction, Right / Q000175:diagnosis / Q000378:metabolism*
chemical_list: C527111:MIRN126 microRNA, human; D035683:MicroRNAs
keywords: hypertension, pulmonary; microRNAs; microvessels; pulmonary heart disease; right ventricular failure