Nitrosative stress drives heart failure with preserved ejection fraction

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Item Type:	Article
Title:	Nitrosative stress drives heart failure with preserved ejection fraction
Creators Name:	Schiattarella, G.G., Altamirano, F., Tong, D., French, K.M., Villalobos, E., Kim, S.Y., Luo, X., Jiang, N., May, H.I., Wang, Z.V., Hill, T.M., Mammen, P.P.A., Huang, J., Lee, D.I., Hahn, V.S., Sharma, K., Kass, D.A., Lavandero, S., 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
Source:	Nature
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Volume:	568
Number:	7752
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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