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Nitrosative stress drives heart failure with preserved ejection fraction

Author

Listed:
  • Gabriele G. Schiattarella

    (University of Texas Southwestern Medical Center
    Federico II University)

  • Francisco Altamirano

    (University of Texas Southwestern Medical Center)

  • Dan Tong

    (University of Texas Southwestern Medical Center)

  • Kristin M. French

    (University of Texas Southwestern Medical Center)

  • Elisa Villalobos

    (University of Texas Southwestern Medical Center)

  • Soo Young Kim

    (University of Texas Southwestern Medical Center)

  • Xiang Luo

    (University of Texas Southwestern Medical Center)

  • Nan Jiang

    (University of Texas Southwestern Medical Center)

  • Herman I. May

    (University of Texas Southwestern Medical Center)

  • Zhao V. Wang

    (University of Texas Southwestern Medical Center)

  • Theodore M. Hill

    (University of Texas Southwestern Medical Center)

  • Pradeep P. A. Mammen

    (University of Texas Southwestern Medical Center)

  • Jian Huang

    (University of Texas Southwestern Medical Center)

  • Dong I. Lee

    (Johns Hopkins School of Medicine)

  • Virginia S. Hahn

    (Johns Hopkins School of Medicine)

  • Kavita Sharma

    (Johns Hopkins School of Medicine)

  • David A. Kass

    (Johns Hopkins School of Medicine)

  • Sergio Lavandero

    (University of Texas Southwestern Medical Center
    University of Chile
    University of Chile)

  • Thomas G. Gillette

    (University of Texas Southwestern Medical Center)

  • Joseph A. Hill

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

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 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.

Suggested Citation

  • Gabriele G. Schiattarella & Francisco Altamirano & Dan Tong & Kristin M. French & Elisa Villalobos & Soo Young Kim & Xiang Luo & Nan Jiang & Herman I. May & Zhao V. Wang & Theodore M. Hill & Pradeep P, 2019. "Nitrosative stress drives heart failure with preserved ejection fraction," Nature, Nature, vol. 568(7752), pages 351-356, April.
    • Handle: RePEc:nat:nature:v:568:y:2019:i:7752:d:10.1038_s41586-019-1100-z
    DOI: 10.1038/s41586-019-1100-z
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    Cited by:

    1. Mingming Zhao & Haoran Wei & Chenze Li & Rui Zhan & Changjie Liu & Jianing Gao & Yaodong Yi & Xiao Cui & Wenxin Shan & Liang Ji & Bing Pan & Si Cheng & Moshi Song & Haipeng Sun & Huidi Jiang & Jun Cai, 2022. "Gut microbiota production of trimethyl-5-aminovaleric acid reduces fatty acid oxidation and accelerates cardiac hypertrophy," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    2. Xueqin Shu & Yingying Shi & Yi Huang & Dan Yu & Baolin Sun, 2023. "Transcription tuned by S-nitrosylation underlies a mechanism for Staphylococcus aureus to circumvent vancomycin killing," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    3. Hannah E Suhrs & Jakob Schroder & Kira B Bové & Naja D Mygind & Daria Frestad & Marie M Michelsen & Theis Lange & Ida Gustafsson & Jens Kastrup & Eva Prescott, 2020. "Inflammation, non-endothelial dependent coronary microvascular function and diastolic function—Are they linked?," PLOS ONE, Public Library of Science, vol. 15(7), pages 1-13, July.
    4. Sara Ranjbarvaziri & Aliya Zeng & Iris Wu & Amara Greer-Short & Farshad Farshidfar & Ana Budan & Emma Xu & Reva Shenwai & Matthew Kozubov & Cindy Li & Melissa Van Pell & Francis Grafton & Charles E Ma, 2024. "Targeting HDAC6 to treat heart failure with preserved ejection fraction in mice," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    5. Bin Li & Wen-Wu Bai & Tao Guo & Zhen-Yu Tang & Xue-Jiao Jing & Ti-Chao Shan & Sen Yin & Ying Li & Fu Wang & Mo-Li Zhu & Jun-Xiu Lu & Yong-Ping Bai & Bo Dong & Peng Li & Shuang-Xi Wang, 2024. "Statins improve cardiac endothelial function to prevent heart failure with preserved ejection fraction through upregulating circRNA-RBCK1," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    6. Mutian Jia & Li Chai & Jie Wang & Mengge Wang & Danhui Qin & Hui Song & Yue Fu & Chunyuan Zhao & Chengjiang Gao & Jihui Jia & Wei Zhao, 2024. "S-nitrosothiol homeostasis maintained by ADH5 facilitates STING-dependent host defense against pathogens," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    7. Yang Cao & Laurent Vergnes & Yu-Chen Wang & Calvin Pan & Karthickeyan Chella Krishnan & Timothy M. Moore & Manuel Rosa-Garrido & Todd H. Kimball & Zhiqiang Zhou & Sarada Charugundla & Christoph D. Rau, 2022. "Sex differences in heart mitochondria regulate diastolic dysfunction," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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