Journal Article

Nitrosative stress drives heart failure with preserved ejection fraction

Schiattarella, Gabriele G., Lavandero, Sergio, Luo, Xiang, Huang, Jian, Villalobos, Elisa, Hill, Joseph A., Mammen, Pradeep P. A., Jiang, Nan, Wang, Zhao V., Sharma, Kavita, Altamirano, Francisco, Lee, Dong I., Tong, Dan, French, Kristin M., Hahn, Virginia S., May, Herman I., Hill, Theodore M., Kass, David A., Gillette, Thomas G., Kim, Soo Young

2019

Overview

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. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/51 / 13/89 / 631/337/470/1463 / 631/80/86/2366 / 692/699/75/230 / 96/1 / 96/106 / 96/63 / 96/95 / Animals / Arginine / Cardiomyocytes / Care and treatment / Congestive heart failure / Diagnosis / Diet / Diet, High-Fat - adverse effects / Disease Models, Animal / Ejection fraction / Endonuclease / Endoribonucleases - metabolism / Evidence-based medicine / Genetic suppression / Health aspects / Heart / Heart failure / Heart Failure - metabolism / Heart Failure - physiopathology / Heart Failure - prevention & control / High fat diet / Humanities and Social Sciences / Humans / Hypertension / Inflammation / Inositol / Kinases / Male / Medical schools / Metabolism / Mice / Mice, Inbred C57BL / Morbidity / multidisciplinary / Musculoskeletal system / Myocardium / Myocytes, Cardiac - enzymology / Myocytes, Cardiac - metabolism / Myocytes, Cardiac - pathology / NG-Nitroarginine methyl ester / NG-Nitroarginine Methyl Ester - pharmacology / Nitric oxide / Nitric Oxide Synthase Type II - antagonists & inhibitors / Nitric Oxide Synthase Type II - deficiency / Nitric Oxide Synthase Type II - genetics / Nitric Oxide Synthase Type II - metabolism / Nitric-oxide synthase / Nitrogen oxides / Nitrosative Stress / Nucleases / Obesity / Pharmacology / Phenotype / Phenotypes / Protein binding / Protein folding / Protein Serine-Threonine Kinases - metabolism / Proteins / Science / Science (multidisciplinary) / Signal Transduction / Splicing / Stroke Volume / X-Box Binding Protein 1 - genetics / X-Box Binding Protein 1 - metabolism