title: Expression of bone morphogenetic protein 4 and its receptors in the remodeling heart.
abstract: OBJECTIVE
  Heart failure is associated with activation of fetal gene programs. Bone morphogenetic proteins (BMPs) regulate embryonic development through interaction with BMP receptors (BMPRs) on the cell surface. We investigated if the expression of BMP4 and its receptors BMPR1a and BMPR2 were activated in post-infarction remodeling and heart failure.
  
  
  METHODS
  Left ventricular biopsies were taken from explanted hearts of patients with end-stage heart failure due to dilated cardiomyopathy (CMP; n=15) or ischemic heart disease (CAD; n=9), and compared with homograft control preparations from organ donors deceased due to non-cardiac causes (n=7). Other samples were taken from patients undergoing coronary artery bypass grafting (CABG; n=11). Mice were subjected to induced infarction by permanent coronary artery ligation or sham operation, and hearts were sampled serially thereafter (n=7 at each time point).
  
  
  RESULTS
  Human and mouse hearts expressed BMP4 and both receptor subtypes. CABG and CMP patients had increased expression of mRNA encoding for BMP4, but unchanged protein. Mouse hearts had increased BMP4 precursor protein 24h after infarction. BMPR1a protein decreased in CAD patients and initially in postinfarcted mouse hearts, but increased again in the latter after two weeks. Human recombinant BMP4 promoted survival after H2O2 injury in HL-1 cells, and also protected adult mouse cardiomyocytes against hypoxia-reoxygenation injury.
  
  
  CONCLUSIONS
  Adult hearts express BMP4, the mRNA increasingly so in patients with coronary artery disease with good cardiac function. BMPRs are downregulated in cardiac remodeling and failure. Recombinant BMP4 has protective effects on cultured cardiomyocytes.
authors.affiliation: Department of Physiology, Institute of Basic Medical Sciences, University of Oslo, Norway.
authors.forename: Xueping
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Physiology, Institute of Basic Medical Sciences, University of Oslo, Norway.
authors.forename: Julia
authors.initials: J
authors.lastname: Sagave
authors.affiliation: Department of Physiology, Institute of Basic Medical Sciences, University of Oslo, Norway; Center for Heart Failure Research, University of Oslo, Norway; Department of Emergency and Intensive Care at the Institute of Clinical Medicine, Oslo University Hospital, Ullevål, Norway. Electronic address: arkady.rutkovskiy@medisin.uio.no.
authors.forename: Arkady
authors.initials: A
authors.lastname: Rutkovskiy
authors.affiliation: Department of Physiology, Institute of Basic Medical Sciences, University of Oslo, Norway; Center for Heart Failure Research, University of Oslo, Norway.
authors.forename: Fred
authors.initials: F
authors.lastname: Haugen
authors.affiliation: Department of Physiology, Institute of Basic Medical Sciences, University of Oslo, Norway; Center for Heart Failure Research, University of Oslo, Norway.
authors.forename: Anton
authors.initials: A
authors.lastname: Baysa
authors.affiliation: Center for Heart Failure Research, University of Oslo, Norway; Bioinformatics Core Facility at the Institute for Medical Informatics, Oslo University Hospital, Ullevål, Norway.
authors.forename: Ståle
authors.initials: S
authors.lastname: Nygård
authors.affiliation: Department of Physiology, Institute of Basic Medical Sciences, University of Oslo, Norway; Center for Heart Failure Research, University of Oslo, Norway.
authors.forename: Gabor
authors.initials: G
authors.lastname: Czibik
authors.affiliation: Center for Heart Failure Research, University of Oslo, Norway; Department of Cardiology, Rikshospitalet University Hospital, Oslo, Norway.
authors.forename: Christen Peder
authors.initials: CP
authors.lastname: Dahl
authors.affiliation: Center for Heart Failure Research, University of Oslo, Norway; Department of Cardiology, Rikshospitalet University Hospital, Oslo, Norway.
authors.forename: Lars
authors.initials: L
authors.lastname: Gullestad
authors.affiliation: Department of Emergency and Intensive Care at the Institute of Clinical Medicine, Oslo University Hospital, Ullevål, Norway.
authors.forename: Jarle
authors.initials: J
authors.lastname: Vaage
authors.affiliation: Department of Physiology, Institute of Basic Medical Sciences, University of Oslo, Norway; Center for Heart Failure Research, University of Oslo, Norway.
authors.forename: Guro
authors.initials: G
authors.lastname: Valen
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics*; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics*; D002311:Cardiomyopathy, Dilated / Q000503:physiopathology; D003324:Coronary Artery Disease / Q000503:physiopathology; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D006333:Heart Failure / Q000503:physiopathology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009203:Myocardial Infarction / Q000503:physiopathology*; D017202:Myocardial Ischemia / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D020257:Ventricular Remodeling; D055815:Young Adult
chemical_list: D055415:Bone Morphogenetic Protein 4; D012333:RNA, Messenger; D052005:Bone Morphogenetic Protein Receptors, Type I; D052006:Bone Morphogenetic Protein Receptors, Type II
keywords: Heart failure; Mouse models of human disease; Remodeling