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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.sup.[omega]-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 1[alpha] (IRE1[alpha]), 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 IRE1[alpha]-XBP1 pathway is a crucial mechanism of cardiomyocyte dysfunction in HFpEF. iNOS-driven dysregulation of the IRE1[alpha]-XBP1 pathway leads to cardiomyocyte dysfunction in mice and recapitulates the systemic and cardiovascular features of human heart failure with preserved ejection fraction., Author(s): Gabriele G. Schiattarella [sup.1] [sup.2] , Francisco Altamirano [sup.1] , Dan Tong [sup.1] , Kristin M. French [sup.1] , Elisa Villalobos [sup.1] , Soo Young Kim [sup.1] , Xiang [...]