| First Author | Schiattarella GG | Year | 2019 |
| Journal | Nature | Volume | 568 |
| Issue | 7752 | Pages | 351-356 |
| PubMed ID | 30971818 | Mgi Jnum | J:311036 |
| Mgi Id | MGI:6384067 | Doi | 10.1038/s41586-019-1100-z |
| Citation | Schiattarella GG, et al. (2019) Nitrosative stress drives heart failure with preserved ejection fraction. Nature 568(7752):351-356 |
| abstractText | 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(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 1alpha (IRE1alpha), 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 IRE1alpha-XBP1 pathway is a crucial mechanism of cardiomyocyte dysfunction in HFpEF. |
