title: Mechanisms of Lipid Accumulation in the Bone Morphogenetic Protein Receptor Type 2 Mutant Right Ventricle.
abstract: In heritable pulmonary arterial hypertension with germline mutation in the bone morphogenetic protein receptor type 2 (BMPR2) gene, right ventricle (RV) dysfunction is associated with RV lipotoxicity; however, the underlying mechanism for lipid accumulation is not known.
  
  
  
  We hypothesized that lipid accumulation in cardiomyocytes with BMPR2 mutation occurs owing to alterations in lipid transport and impaired fatty acid oxidation (FAO), which is exacerbated by a high-lipid (Western) diet (WD).
  
  
  
  We used a transgenic mouse model of pulmonary arterial hypertension with mutant BMPR2 and generated a cardiomyocyte cell line with BMPR2 mutation. Electron microscopy and metabolomic analysis were performed on mouse RVs.
  
  
  
  By metabolomics analysis, we found an increase in long-chain fatty acids in BMPR2 mutant mouse RVs compared with controls, which correlated with cardiac index. BMPR2-mutant cardiomyocytes had increased lipid compared with controls. Direct measurement of FAO in the WD-fed BMPR2-mutant RV showed impaired palmitate-linked oxygen consumption, and metabolomics analysis showed reduced indices of FAO. Using both mutant BMPR2 mouse RVs and cardiomyocytes, we found an increase in the uptake of (14)C-palmitate and fatty acid transporter CD36 that was further exacerbated by WD.
  
  
  
  Taken together, our data suggest that impaired FAO and increased expression of the lipid transporter CD36 are key mechanisms underlying lipid deposition in the BMPR2-mutant RV, which are exacerbated in the presence of dietary lipids. These findings suggest important features leading to RV lipotoxicity in pulmonary arterial hypertension and may point to novel areas of therapeutic intervention.
authors.affiliation: 1 Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Megha H
authors.initials: MH
authors.lastname: Talati
authors.affiliation: 2 Division of Cardiology.
authors.forename: Evan L
authors.initials: EL
authors.lastname: Brittain
authors.affiliation: 1 Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.|3 Department of Pharmacology.
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Fessel
authors.affiliation: 1 Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Niki
authors.initials: N
authors.lastname: Penner
authors.affiliation: 4 Department of Pathology, Microbiology, and Immunology.
authors.forename: James
authors.initials: J
authors.lastname: Atkinson
authors.affiliation: 1 Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Mitch
authors.initials: M
authors.lastname: Funke
authors.affiliation: 5 Department of Anesthesiology.
authors.forename: Carrie
authors.initials: C
authors.lastname: Grueter
authors.affiliation: 4 Department of Pathology, Microbiology, and Immunology.|6 Department of Cancer Biology, and.
authors.forename: W Gray
authors.initials: WG
authors.lastname: Jerome
authors.affiliation: 7 Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Michael
authors.initials: M
authors.lastname: Freeman
authors.affiliation: 1 Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: John H
authors.initials: JH
authors.lastname: Newman
authors.affiliation: 1 Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: James
authors.initials: J
authors.lastname: West
authors.affiliation: 1 Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Anna R
authors.initials: AR
authors.lastname: Hemnes
mesh_terms: D000818:Animals; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics* / Q000502:physiology; D002460:Cell Line; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism; D006352:Heart Ventricles / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics; D008055:Lipids / Q000032:analysis*; D055432:Metabolomics; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D032383:Myocytes, Cardiac / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D008055:Lipids; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II
keywords: fatty acid oxidation; fatty acid transporter (CD36); lipotoxic cardiomyopathy; pulmonary arterial hypertension; right ventricular lipotoxicity