Evidence for right ventricular lipotoxicity in heritable pulmonary arterial hypertension

Am J Respir Crit Care Med. 2014 Feb 1;189(3):325-34. doi: 10.1164/rccm.201306-1086OC.


Rationale: Shorter survival in heritable pulmonary arterial hypertension (HPAH), often due to BMPR2 mutation, has been described in association with impaired right ventricle (RV) compensation. HPAH animal models are insulin resistant, and cells with BMPR2 mutation have impaired fatty acid oxidation, but whether these findings affect the RV in HPAH is unknown.

Objectives: To test the hypothesis that BMPR2 mutation impairs RV hypertrophic responses in association with lipid deposition.

Methods: RV hypertrophy was assessed in two models of mutant Bmpr2 expression, smooth muscle-specific (Sm22(R899X)) and universal expression (Rosa26(R899X)). Littermate control mice underwent the same stress using pulmonary artery banding (Low-PAB). Lipid content was assessed in rodent and human HPAH RVs and in Rosa26(R899X) mice after metformin administration. RV microarrays were performed using human HPAH and control subjects.

Results: RV/(left ventricle + septum) did not rise directly in proportion to RV systolic pressure in Rosa26(R899X) but did in Sm22(R899X) (P < 0.05). Rosa26(R899X) RVs demonstrated intracardiomyocyte triglyceride deposition not present in Low-PAB (P < 0.05). RV lipid deposition was identified in human HPAH RVs but not in controls. Microarray analysis demonstrated defects in fatty acid oxidation in human HPAH RVs. Metformin in Rosa26(R899X) mice resulted in reduced RV lipid deposition.

Conclusions: These data demonstrate that Bmpr2 mutation affects RV stress responses in a transgenic rodent model. Impaired RV hypertrophy and triglyceride and ceramide deposition are present as a function of RV mutant Bmpr2 in mice; fatty acid oxidation impairment in human HPAH RVs may underlie this finding. Further study of how BMPR2 mediates RV lipotoxicity is warranted.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Bone Morphogenetic Protein Receptors, Type II / genetics*
  • Case-Control Studies
  • Ceramides / metabolism*
  • Familial Primary Pulmonary Hypertension
  • Genetic Markers
  • Humans
  • Hypertension, Pulmonary / complications
  • Hypertension, Pulmonary / genetics*
  • Hypertrophy, Right Ventricular / etiology
  • Hypertrophy, Right Ventricular / genetics
  • Hypertrophy, Right Ventricular / metabolism*
  • Lipolysis*
  • Mice
  • Mice, Transgenic
  • Mutation
  • Oligonucleotide Array Sequence Analysis
  • Oxidation-Reduction
  • Triglycerides / metabolism*


  • Biomarkers
  • Ceramides
  • Genetic Markers
  • Triglycerides
  • Bmpr2 protein, mouse
  • Bone Morphogenetic Protein Receptors, Type II