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Nature. 2019 Apr;568(7752):351-356. doi: 10.1038/s41586-019-1100-z. Epub 2019 Apr 10.

Nitrosative stress drives heart failure with preserved ejection fraction.

Author information

1
Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
2
Division of Cardiology, Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.
3
Division of Cardiology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.
4
Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical & Pharmaceutical Sciences and Faculty of Medicine, University of Chile, Santiago, Chile.
5
Center for Molecular Studies of the Cell (CEMC), Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Santiago, Chile.
6
Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA. joseph.hill@utsouthwestern.edu.
7
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA. joseph.hill@utsouthwestern.edu.

Abstract

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 Nω-nitro-L-arginine 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 1α (IRE1α), 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 IRE1α-XBP1 pathway is a crucial mechanism of cardiomyocyte dysfunction in HFpEF.

PMID:
30971818
DOI:
10.1038/s41586-019-1100-z

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