Document Detail


Evidence for right ventricular lipotoxicity in heritable pulmonary arterial hypertension.
MedLine Citation:
PMID:  24274756     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Anna R Hemnes; Evan L Brittain; Aaron W Trammell; Joshua P Fessel; Eric D Austin; Niki Penner; Karen B Maynard; Linda Gleaves; Megha Talati; Tarek Absi; Thomas Disalvo; James West
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  American journal of respiratory and critical care medicine     Volume:  189     ISSN:  1535-4970     ISO Abbreviation:  Am. J. Respir. Crit. Care Med.     Publication Date:  2014 Feb 
Date Detail:
Created Date:  2014-02-03     Completed Date:  2014-04-04     Revised Date:  2014-04-30    
Medline Journal Info:
Nlm Unique ID:  9421642     Medline TA:  Am J Respir Crit Care Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  325-34     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Biological Markers / metabolism
Bone Morphogenetic Protein Receptors, Type II / genetics*
Case-Control Studies
Ceramides / metabolism*
Genetic Markers
Humans
Hypertension, Pulmonary / complications,  genetics*
Hypertrophy, Right Ventricular / etiology,  genetics,  metabolism*
Lipolysis*
Mice
Mice, Transgenic
Mutation
Oligonucleotide Array Sequence Analysis
Oxidation-Reduction
Triglycerides / metabolism*
Grant Support
ID/Acronym/Agency:
1P01HL108800/HL/NHLBI NIH HHS; HL82694/HL/NHLBI NIH HHS; HL95797/HL/NHLBI NIH HHS; K08 HL093363/HL/NHLBI NIH HHS; K23 HL0987431/HL/NHLBI NIH HHS; P01 HL108800/HL/NHLBI NIH HHS; T32 HL007411/HL/NHLBI NIH HHS; T32 HL094296/HL/NHLBI NIH HHS; U24 DK059637/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Biological Markers; 0/Ceramides; 0/Genetic Markers; 0/Triglycerides; EC 2.7.11.30/Bmpr2 protein, mouse; EC 2.7.11.30/Bone Morphogenetic Protein Receptors, Type II
Comments/Corrections
Comment In:
Am J Respir Crit Care Med. 2014 Feb 1;189(3):247-9   [PMID:  24484329 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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