Nitrosative stress drives heart failure with preserved ejection fraction

• Published in: Nature (London) Vol. 568; no. 7752; pp. 351 - 356
• Main Authors: Schiattarella, Gabriele G, Altamirano, Francisco, Tong, Dan, French, Kristin M, Villalobos, Elisa, Kim, Soo Young, Luo, Xiang, Jiang, Nan, May, Herman I, Wang, Zhao V, Hill, Theodore M, Mammen, Pradeep P A, Huang, Jian, Lee, Dong I, Hahn, Virginia S, Sharma, Kavita, Kass, David A, Lavandero, Sergio, Gillette, Thomas G, Hill, Joseph A
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.04.2019
• Subjects: Animals; Arginine; Cardiomyocytes; Care and treatment; Congestive heart failure; Diagnosis; Diet; Diet, High-Fat - adverse effects; Disease Models, Animal; Ejection fraction; Endonuclease; Endoribonucleases - metabolism; Evidence-based medicine; Genetic suppression; Health aspects; Heart; Heart failure; Heart Failure - metabolism; Heart Failure - physiopathology; Heart Failure - prevention & control; High fat diet; Humans; Hypertension; Inflammation; Inositol; Kinases; Male; Medical schools; Metabolism; Mice; Mice, Inbred C57BL; Morbidity; Musculoskeletal system; Myocardium; Myocytes, Cardiac - enzymology; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; NG-Nitroarginine methyl ester; NG-Nitroarginine Methyl Ester - pharmacology; Nitric oxide; Nitric Oxide Synthase Type II - antagonists & inhibitors; Nitric Oxide Synthase Type II - deficiency; Nitric Oxide Synthase Type II - genetics; Nitric Oxide Synthase Type II - metabolism; Nitric-oxide synthase; Nitrogen oxides; Nitrosative Stress; Nucleases; Obesity; Pharmacology; Phenotype; Phenotypes; Protein binding; Protein folding; Protein Serine-Threonine Kinases - metabolism; Proteins; Signal Transduction; Splicing; Stroke Volume; X-Box Binding Protein 1 - genetics; X-Box Binding Protein 1 - metabolism
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-019-1100-z

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 -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.