Journal Article

Evidence for Right Ventricular Lipotoxicity in Heritable Pulmonary Arterial Hypertension

Fessel, Joshua P., Penner, Niki, Gleaves, Linda, Absi, Tarek, Trammell, Aaron W., Maynard, Karen B., DiSalvo, Thomas, Hemnes, Anna R., Brittain, Evan L., West, James, Talati, Megha, Austin, Eric D.

2014

Overview

Abstract 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 (Sm22R899X) and universal expression (Rosa26R899X). 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 Rosa26R899X 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 Rosa26R899X but did in Sm22R899X (P < 0.05). Rosa26R899X 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 Rosa26R899X 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.

• Publisher: Oxford University Press,American Thoracic Society
• Subject: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy / Animals / Arrays / Biological and medical sciences / Biomarkers - metabolism / Bone Morphogenetic Protein Receptors, Type II - genetics / Cardiology. Vascular system / Case-Control Studies / Ceramides - metabolism / Familial Primary Pulmonary Hypertension / Fatty acids / Genetic Markers / Heart / Heart failure / Heart failure, cardiogenic pulmonary edema, cardiac enlargement / Hemodynamics / Humans / Hypertension, Pulmonary - complications / Hypertension, Pulmonary - genetics / Hypertrophy, Right Ventricular - etiology / Hypertrophy, Right Ventricular - genetics / Hypertrophy, Right Ventricular - metabolism / Hypotheses / Insulin resistance / Intensive care medicine / Lipids / Lipolysis / Medical sciences / Metabolism / Mice / Mice, Transgenic / Mortality / Mutation / Oligonucleotide Array Sequence Analysis / Original / Oxidation / Oxidation-Reduction / Pneumology / Pulmonary arteries / Pulmonary hypertension / Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases / Smooth muscle / Triglycerides - metabolism / Variance analysis