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 and Joseph A. Hill ()
Additional contact information
Gabriele G. Schiattarella: University of Texas Southwestern Medical Center
Francisco Altamirano: University of Texas Southwestern Medical Center
Dan Tong: University of Texas Southwestern Medical Center
Kristin M. French: University of Texas Southwestern Medical Center
Elisa Villalobos: University of Texas Southwestern Medical Center
Soo Young Kim: University of Texas Southwestern Medical Center
Xiang Luo: University of Texas Southwestern Medical Center
Nan Jiang: University of Texas Southwestern Medical Center
Herman I. May: University of Texas Southwestern Medical Center
Zhao V. Wang: University of Texas Southwestern Medical Center
Theodore M. Hill: University of Texas Southwestern Medical Center
Pradeep P. A. Mammen: University of Texas Southwestern Medical Center
Jian Huang: University of Texas Southwestern Medical Center
Dong I. Lee: Johns Hopkins School of Medicine
Virginia S. Hahn: Johns Hopkins School of Medicine
Kavita Sharma: Johns Hopkins School of Medicine
David A. Kass: Johns Hopkins School of Medicine
Sergio Lavandero: University of Texas Southwestern Medical Center
Thomas G. Gillette: University of Texas Southwestern Medical Center
Joseph A. Hill: University of Texas Southwestern Medical Center

Nature, 2019, vol. 568, issue 7752, 351-356

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1100-z

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