title: A miR-208-Mef2 axis drives the decompensation of right ventricular function in pulmonary hypertension.
abstract: BACKGROUND
  Right ventricular (RV) failure is a major cause of morbidity and mortality in pulmonary hypertension, but its mechanism remains unknown. Myocyte enhancer factor 2 (Mef2) has been implicated in RV development, regulating metabolic, contractile, and angiogenic genes. Moreover, Mef2 regulates microRNAs that have emerged as important determinants of cardiac development and disease, but for which the role in RV is still unclear.
  
  
  OBJECTIVE
  We hypothesized a critical role of a Mef2-microRNAs axis in RV failure.
  
  
  RESULTS
  In a rat pulmonary hypertension model (monocrotaline), we studied RV free wall tissues from rats with normal, compensated, and decompensated RV hypertrophy, carefully defined based on clinically relevant parameters, including RV systolic and end-diastolic pressures, cardiac output, RV size, and morbidity. Mef2c expression was sharply increased in compensating phase of RVH tissues but was lost in decompensation phase of RVH. An unbiased screening of microRNAs in our model resulted to a short microRNA signature of decompensated RV failure, which included the myocardium-specific miR-208, which was progressively downregulated as RV failure progressed, in contrast to what is described in left ventricular failure. With mechanistic in vitro experiments using neonatal and adult RV cardiomyocytes, we showed that miR-208 inhibition, as well as tumor necrosis factor-α, activates the complex mediator of transcription 13/nuclear receptor corepressor 1 axis, which in turn promotes Mef2 inhibition, closing a self-limiting feedback loop, driving the transition from compensating phase of RVH toward decompensation phase of RVH. In our model, serum tumor necrosis factor-α levels progressively increased with time while serum miR-208 levels decreased, mirroring its levels in RV myocardium.
  
  
  CONCLUSIONS
  We describe an RV-specific mechanism for heart failure, which could potentially lead to new biomarkers and therapeutic targets.
authors.affiliation: From the Department of Medicine, University of Alberta, Edmonton, Canada (R.P., G.S., V.G., P.D., A.H., E.D.M.); and Pulmonary Hypertension Research Group, Department of Medicine, Laval University, CRIUCPQ, Québec City, QC, Canada (S.P., S.B.).
authors.forename: Roxane
authors.initials: R
authors.lastname: Paulin
authors.affiliation: From the Department of Medicine, University of Alberta, Edmonton, Canada (R.P., G.S., V.G., P.D., A.H., E.D.M.); and Pulmonary Hypertension Research Group, Department of Medicine, Laval University, CRIUCPQ, Québec City, QC, Canada (S.P., S.B.).
authors.forename: Gopinath
authors.initials: G
authors.lastname: Sutendra
authors.affiliation: From the Department of Medicine, University of Alberta, Edmonton, Canada (R.P., G.S., V.G., P.D., A.H., E.D.M.); and Pulmonary Hypertension Research Group, Department of Medicine, Laval University, CRIUCPQ, Québec City, QC, Canada (S.P., S.B.).
authors.forename: Vikram
authors.initials: V
authors.lastname: Gurtu
authors.affiliation: From the Department of Medicine, University of Alberta, Edmonton, Canada (R.P., G.S., V.G., P.D., A.H., E.D.M.); and Pulmonary Hypertension Research Group, Department of Medicine, Laval University, CRIUCPQ, Québec City, QC, Canada (S.P., S.B.).
authors.forename: Peter
authors.initials: P
authors.lastname: Dromparis
authors.affiliation: From the Department of Medicine, University of Alberta, Edmonton, Canada (R.P., G.S., V.G., P.D., A.H., E.D.M.); and Pulmonary Hypertension Research Group, Department of Medicine, Laval University, CRIUCPQ, Québec City, QC, Canada (S.P., S.B.).
authors.forename: Alois
authors.initials: A
authors.lastname: Haromy
authors.affiliation: From the Department of Medicine, University of Alberta, Edmonton, Canada (R.P., G.S., V.G., P.D., A.H., E.D.M.); and Pulmonary Hypertension Research Group, Department of Medicine, Laval University, CRIUCPQ, Québec City, QC, Canada (S.P., S.B.).
authors.forename: Steeve
authors.initials: S
authors.lastname: Provencher
authors.affiliation: From the Department of Medicine, University of Alberta, Edmonton, Canada (R.P., G.S., V.G., P.D., A.H., E.D.M.); and Pulmonary Hypertension Research Group, Department of Medicine, Laval University, CRIUCPQ, Québec City, QC, Canada (S.P., S.B.).
authors.forename: Sebastien
authors.initials: S
authors.lastname: Bonnet
authors.affiliation: From the Department of Medicine, University of Alberta, Edmonton, Canada (R.P., G.S., V.G., P.D., A.H., E.D.M.); and Pulmonary Hypertension Research Group, Department of Medicine, Laval University, CRIUCPQ, Québec City, QC, Canada (S.P., S.B.). em2@ualberta.ca.
authors.forename: Evangelos D
authors.initials: ED
authors.lastname: Michelakis
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000473:pathology; D064326:MEF2 Transcription Factors / Q000096:biosynthesis*; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis*; D032383:Myocytes, Cardiac / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D016278:Ventricular Function, Right / Q000502:physiology*
chemical_list: D064326:MEF2 Transcription Factors; C569395:MIRN208 microRNA, rat; D035683:MicroRNAs
keywords: biomarkers; hypertension, pulmonary; inflammation; metabolism; microRNAs