Natriuretic peptide receptor C contributes to disproportionate right ventricular hypertrophy in a rodent model of obesity-induced heart failure with preserved ejection fraction with pulmonary hypertension

Vineet Agrawal, Niki Fortune, Sheeline Yu, Julio Fuentes, Fubiao Shi, David Nichols, Linda Gleaves, Emily Poovey, Thomas J. Wang, Evan L. Brittain, Sheila Collins, James D. West, Anna R. Hemnes

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Heart failure with preserved ejection fraction (HFpEF) currently has no therapies that improve mortality. Right ventricular dysfunction and pulmonary hypertension are common in HFpEF, and thought to be driven by obesity and metabolic syndrome. Thus, we hypothesized that an animal model of obesity-induced HFpEF with pulmonary hypertension would provide insight into the pathogenesis of right ventricular failure in HFpEF. Two strains of mice, one susceptible (AKR) and one resistant (C3H) to obesity-induced HFpEF, were fed high fat (60% fat) or control diet for 0, 2, or 20 weeks and evaluated by cardiac catheterization and echocardiography for development of right ventricular dysfunction, pulmonary hypertension, and HFpEF. AKR, but not C3H, mice developed right ventricular dysfunction, pulmonary hypertension, and HFpEF. NPRC, which antagonizes beneficial natriuretic peptide signaling, was found in RNA sequencing to be the most differentially upregulated gene in the right ventricle, but not left ventricle or lung, of AKR mice that developed pulmonary hypertension and HFpEF. Overexpression of NPRC in H9C2 cells increased basal cell size and increased expression of hypertrophic genes, MYH7 and NPPA. In conclusion, we have shown that NPRC contributes to right ventricular modeling in obesity-induced pulmonary hypertension-HFpEF by increasing cardiomyocyte hypertrophy. NPRC may represent a promising therapeutic target for right ventricular dysfunction in pulmonary hypertension-HFpEF.

Original languageEnglish (US)
JournalPulmonary Circulation
Volume9
Issue number4
DOIs
StatePublished - 2019
Externally publishedYes

Keywords

  • congestive heart failure
  • diabetes and dyslipidemias
  • natriuretic peptides
  • obesity and metabolic syndrome
  • pulmonary hypertension
  • right ventricle function and dysfunction

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

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