Nitrosative stress drives heart failure with preserved ejection fraction

Gabriele G. Schiattarella, Francisco Altamirano, Dan Tong, Kristin M. French, Elisa Villalobos, Soo Young Kim, Xiang Luo, Nan Jiang, Herman I. May, Zhao V. Wang, Theodore M. Hill, Pradeep P.A. Mammen, Jian Huang, Dong I. Lee, Virginia S. Hahn, Kavita Sharma, David A. Kass, Sergio Lavandero, Thomas G. Gillette, Joseph A. Hill

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)351-356
Number of pages6
JournalNature
Volume568
Issue number7752
DOIs
StatePublished - Apr 18 2019

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    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., & Hill, J. A. (2019). Nitrosative stress drives heart failure with preserved ejection fraction. Nature, 568(7752), 351-356. https://doi.org/10.1038/s41586-019-1100-z