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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 I; Hahn, Virginia S; Sharma, Kavita; Kass, David A; Lavandero, Sergio; Gillette, Thomas G; Hill, Joseph A.
Afiliação
  • Schiattarella GG; Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Altamirano F; Division of Cardiology, Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy.
  • Tong D; Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • French KM; Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Villalobos E; Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Kim SY; Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Luo X; Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Jiang N; Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • May HI; Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Wang ZV; Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Hill TM; Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Mammen PPA; Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Huang J; Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Lee DI; Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Hahn VS; Division of Cardiology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.
  • Sharma K; Division of Cardiology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.
  • Kass DA; Division of Cardiology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.
  • Lavandero S; Division of Cardiology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.
  • Gillette TG; Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Hill JA; Advanced Center for Chronic Diseases (ACCDiS), Faculty of Chemical & Pharmaceutical Sciences and Faculty of Medicine, University of Chile, Santiago, Chile.
Nature ; 568(7752): 351-356, 2019 04.
Article em En | MEDLINE | ID: mdl-30971818
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Volume Sistólico / Estresse Nitrosativo / Insuficiência Cardíaca Idioma: En Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Volume Sistólico / Estresse Nitrosativo / Insuficiência Cardíaca Idioma: En Ano de publicação: 2019 Tipo de documento: Article