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

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 MacKay, Xiaomei Song, James R Priest, Gretchen Argast, Mohammad A. Mandegar, Timothy Hoey and Jin Yang ()
Additional contact information
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

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45440-7

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