Artículo de revista
Nitrosative stress drives heart failure with preserved ejection fraction
Fecha
2019Registro en:
Nature . 2019 April ; 568(7752): 351–356
14764687
00280836
10.1038/s41586-019-1100-z
Autor
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
Huang, Jian
Lee, Dong I.
Hahn, Virginia
Sharma, Kavita
Kass, David A.
Lavandero González, Sergio
Gillette, Thomas G.
Hill, Joseph A.
Institución
Resumen
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.