Journal
NATURE
Volume 568, Issue 7752, Pages 351-+Publisher
NATURE RESEARCH
DOI: 10.1038/s41586-019-1100-z
Keywords
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Categories
Funding
- NIH [HL-120732, HL-128215, HL-126012, F32HL136151, F32HL142244, 2T32HL007227-41, HL-135827, HL-119012, R01-HL102478]
- American Heart Association (AHA) [16POST30680016, 16PRE29660003, 14SFRN20510023, 14SFRN20670003, 16SFRN28620000]
- AHA
- Theodore and Beulah Beasley Foundation [18POST34060230]
- University Federico II of Naples
- Fondation Leducq TransAtlantic Network of Excellence [11CVD04]
- Cancer Prevention and Research Institute of Texas [RP110486P3]
- Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center [U54-HD087351]
- Fondo Nacional de Desarrollo Cientifico y Tecnologico [FONDAP 15130011]
- BioTechne Grant Foundation
- Compagnia di San Paolo STAR program
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Heart failure with preserved ejection fraction (HFpEF) is a common syndrome with high morbidity and mortality for which there are no evidence-based therapies. Here we report that concomitant metabolic and hypertensive stress in mice-elicited by a combination of high-fat diet and inhibition of constitutive nitric oxide synthase using N-omega-nitro-larginine methyl ester (L-NAME)-recapitulates the numerous systemic and cardiovascular features of HFpEF in humans. Expression of one of the unfolded protein response effectors, the spliced form of X-box-binding protein 1 (XBP1s), was reduced in the myocardium of our rodent model and in humans with HFpEF. Mechanistically, the decrease in XBP1s resulted from increased activity of inducible nitric oxide synthase (iNOS) and S-nitrosylation of the endonuclease inositol-requiring protein 1 alpha (IRE1 alpha), culminating in defective XBP1 splicing. Pharmacological or genetic suppression of iNOS, or cardiomyocyte-restricted overexpression of XBP1s, each ameliorated the HFpEF phenotype. We report that iNOS-driven dysregulation of the IRE1 alpha-XBP1 pathway is a crucial mechanism of cardiomyocyte dysfunction in HFpEF.
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