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Targeting HDAC6 to treat heart failure with preserved ejection fraction in mice

Author

Listed:
  • Sara Ranjbarvaziri

    (Tenaya Therapeutics)

  • Aliya Zeng

    (Tenaya Therapeutics)

  • Iris Wu

    (Tenaya Therapeutics)

  • Amara Greer-Short

    (Tenaya Therapeutics)

  • Farshad Farshidfar

    (Tenaya Therapeutics)

  • Ana Budan

    (Tenaya Therapeutics)

  • Emma Xu

    (Tenaya Therapeutics)

  • Reva Shenwai

    (Tenaya Therapeutics)

  • Matthew Kozubov

    (Tenaya Therapeutics)

  • Cindy Li

    (Tenaya Therapeutics)

  • Melissa Van Pell

    (Tenaya Therapeutics)

  • Francis Grafton

    (Tenaya Therapeutics)

  • Charles E MacKay

    (Tenaya Therapeutics)

  • Xiaomei Song

    (Tenaya Therapeutics)

  • James R Priest

    (Tenaya Therapeutics)

  • Gretchen Argast

    (Tenaya Therapeutics)

  • Mohammad A. Mandegar

    (Tenaya Therapeutics)

  • Timothy Hoey

    (Tenaya Therapeutics)

  • Jin Yang

    (Tenaya Therapeutics)

Abstract

Heart failure with preserved ejection fraction (HFpEF) poses therapeutic challenges due to the limited treatment options. Building upon our previous research that demonstrates the efficacy of histone deacetylase 6 (HDAC6) inhibition in a genetic cardiomyopathy model, we investigate HDAC6’s role in HFpEF due to their shared mechanisms of inflammation and metabolism. Here, we show that inhibiting HDAC6 with TYA-018 effectively reverses established heart failure and its associated symptoms in male HFpEF mouse models. Additionally, in male mice lacking Hdac6 gene, HFpEF progression is delayed and they are resistant to TYA-018’s effects. The efficacy of TYA-018 is comparable to a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and the combination shows enhanced effects. Mechanistically, TYA-018 restores gene expression related to hypertrophy, fibrosis, and mitochondrial energy production in HFpEF heart tissues. Furthermore, TYA-018 also inhibits activation of human cardiac fibroblasts and enhances mitochondrial respiratory capacity in cardiomyocytes. In this work, our findings show that HDAC6 impacts on heart pathophysiology and is a promising target for HFpEF treatment.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45440-7
    DOI: 10.1038/s41467-024-45440-7
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    References listed on IDEAS

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    1. Jin Yang & Konstantinos Savvatis & Jong Seok Kang & Peidong Fan & Hongyan Zhong & Karen Schwartz & Vivian Barry & Amanda Mikels-Vigdal & Serge Karpinski & Dmytro Kornyeyev & Joanne Adamkewicz & Xuhui , 2016. "Targeting LOXL2 for cardiac interstitial fibrosis and heart failure treatment," Nature Communications, Nature, vol. 7(1), pages 1-15, December.
    2. 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.
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