Nitrosative stress drives heart failure with preserved ejection fraction
| Autor: | Nan Jiang, Sergio Lavandero, Kristin M. French, Thomas G. Gillette, Kavita Sharma, Virginia S. Hahn, Gabriele G. Schiattarella, David A. Kass, Dong I. Lee, Dan Tong, Soo Young Kim, Zhao V. Wang, Elisa Villalobos, Xiang Luo, Joseph A. Hill, Jian Huang, Francisco Altamirano, Pradeep P.A. Mammen, Theodore M. Hill, Herman I. May |
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| Přispěvatelé: | Schiattarella, G. G., Altamirano, F., Tong, D., French, K. M., Villalobos, E., Kim, S. Y., Luo, X., Jiang, N., May, H. I., Wang, Z. V., Hill, T. M., Mammen, P. P. A., Huang, J., Lee, D. I., Hahn, V. S., Sharma, K., Kass, D. A., Lavandero, S., Gillette, T. G., Hill, J. A. |
| Rok vydání: | 2019 |
| Předmět: |
Male
X-Box Binding Protein 1 0301 basic medicine medicine.medical_specialty XBP1 Protein Serine-Threonine Kinase Nitrosative Stre Nitric Oxide Synthase Type II 030204 cardiovascular system & hematology Diet High-Fat Mice 03 medical and health sciences 0302 clinical medicine Internal medicine medicine Myocyte Myocytes Cardiac Endoribonuclease Heart Failure Multidisciplinary Ejection fraction biology Animal business.industry Stroke Volume Stroke volume Mice Inbred C57BL Nitric oxide synthase Disease Models Animal NG-Nitroarginine Methyl Ester Phenotype 030104 developmental biology Endocrinology biology.protein Unfolded protein response Signal transduction business Heart failure with preserved ejection fraction Human Signal Transduction |
| Zdroj: | Nature. 568:351-356 |
| ISSN: | 1476-4687 0028-0836 |
| Popis: | 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 Nω-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. iNOS-driven dysregulation of the IRE1α–XBP1 pathway leads to cardiomyocyte dysfunction in mice and recapitulates the systemic and cardiovascular features of human heart failure with preserved ejection fraction. |
| Databáze: | OpenAIRE |
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