@article{01b0893d7c7f418a95cef9f664ef5d8d,
title = "Nitrosative stress drives heart failure with preserved ejection fraction",
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. ",
author = "Schiattarella, {Gabriele G.} and Francisco Altamirano and Dan Tong and French, {Kristin M.} and Elisa Villalobos and Kim, {Soo Young} and Xiang Luo and Nan Jiang and May, {Herman I.} and Wang, {Zhao V.} and Hill, {Theodore M.} and Mammen, {Pradeep P.A.} and Jian Huang and Lee, {Dong I.} and Hahn, {Virginia S.} and Kavita Sharma and Kass, {David A.} and Sergio Lavandero and Gillette, {Thomas G.} and Hill, {Joseph A.}",
note = "Funding Information: Acknowledgements This work was supported by grants from NIH: HL-120732 (J.A.H.), HL-128215 (J.A.H.), HL-126012 (J.A.H.), F32HL136151 (K.M.F.), F32HL142244 (D.T.), 2T32HL007227-41 (V.S.H.), HL-135827 (D.A.K.), HL-119012 (D.A.K.), R01-HL102478 (P.P.A.M.), the American Heart Association (AHA): 16POST30680016 (F.A.), 16PRE29660003 (S.Y.K.), 14SFRN20510023 (J.A.H.), 14SFRN20670003 (J.A.H.) and 16SFRN28620000 (K.S. and D.A.K.), AHA and the Theodore and Beulah Beasley Foundation 18POST34060230 (G.G.S.), University Federico II of Naples and Compagnia di San Paolo STAR program (G.G.S.), Fondation Leducq TransAtlantic Network of Excellence11CVD04 (J.A.H.), Cancer Prevention and Research Institute of Texas RP110486P3 (J.A.H.), Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center U54-HD087351 (P.P.A.M.) and by Fondo Nacional de Desarrollo Cient{\'i}fico y Tecnol{\'o}gico, FONDAP 15130011 (S.L.). We thank G. S. Hotamisligil and L. Yang for providing ERN1 wild-type and ERN1 M1+M2-expressing adenoviruses. We thank A. Rosenberg for his help with the ProteinSimple capillary immunoassay analysis (partly supported by The BioTechne Grant Foundation). Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2019",
month = apr,
day = "18",
doi = "10.1038/s41586-019-1100-z",
language = "English (US)",
volume = "568",
pages = "351--356",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7752",
}