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Nitrosative stress drives heart failure with preserved ejection fraction

Item Type:Article
Title:Nitrosative stress drives heart failure with preserved ejection fraction
Creators Name:Schiattarella, G.G. and Altamirano, F. and Tong, D. and French, K.M. and Villalobos, E. and Kim, S.Y. and Luo, X. and Jiang, N. and May, H.I. and Wang, Z.V. and Hill, T.M. and Mammen, P.P.A. and Huang, J. and Lee, D.I. and Hahn, V.S. and Sharma, K. and Kass, D.A. and Lavandero, S. and Gillette, T.G. and Hill, J.A.
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 N(ω)-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.
Keywords:Animal Disease Models, Cardiac Myocytes, Endoribonucleases, Heart Failure, High-Fat Diet, Inbred C57BL Mice, NG-Nitroarginine Methyl Ester, Nitric Oxide Synthase Type II, Nitrosative Stress, Phenotype, Protein-Serine-Threonine Kinases, Signal Transduction, Stroke Volume, X-Box Binding Protein 1, Animals, Mice
Publisher:Nature Publishing Group
Page Range:351-356
Date:18 April 2019
Official Publication:https://doi.org/10.1038/s41586-019-1100-z
PubMed:View item in PubMed

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