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 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 351-356 |
| Number of pages | 6 |
| Journal | Nature |
| Volume | 568 |
| Issue number | 7752 |
| DOIs | |
| State | Published - Apr 18 2019 |
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ASJC Scopus subject areas
- General
Cite this
Nitrosative stress drives heart failure with preserved ejection fraction. / 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; Hahn, Virginia S.; Sharma, Kavita; Kass, David A; Lavandero, Sergio; Gillette, Thomas G.; Hill, Joseph A.
In: Nature, Vol. 568, No. 7752, 18.04.2019, p. 351-356.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Nitrosative stress drives heart failure with preserved ejection fraction
AU - Schiattarella, Gabriele G.
AU - Altamirano, Francisco
AU - Tong, Dan
AU - French, Kristin M.
AU - Villalobos, Elisa
AU - Kim, Soo Young
AU - Luo, Xiang
AU - Jiang, Nan
AU - May, Herman I.
AU - Wang, Zhao V.
AU - Hill, Theodore M.
AU - Mammen, Pradeep P.A.
AU - Huang, Jian
AU - Lee, Dong
AU - Hahn, Virginia S.
AU - Sharma, Kavita
AU - Kass, David A
AU - Lavandero, Sergio
AU - Gillette, Thomas G.
AU - Hill, Joseph A.
PY - 2019/4/18
Y1 - 2019/4/18
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85064274841&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85064274841&partnerID=8YFLogxK
U2 - 10.1038/s41586-019-1100-z
DO - 10.1038/s41586-019-1100-z
M3 - Article
C2 - 30971818
AN - SCOPUS:85064274841
VL - 568
SP - 351
EP - 356
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7752
ER -