학술논문
Targeting HDAC6 to treat heart failure with preserved ejection fraction in mice.
Document Type
Academic Journal
Author
Ranjbarvaziri S; Tenaya Therapeutics, South San Francisco, CA, USA.; Zeng A; Tenaya Therapeutics, South San Francisco, CA, USA.; Wu I; Tenaya Therapeutics, South San Francisco, CA, USA.; Greer-Short A; Tenaya Therapeutics, South San Francisco, CA, USA.; Farshidfar F; Tenaya Therapeutics, South San Francisco, CA, USA.; Budan A; Tenaya Therapeutics, South San Francisco, CA, USA.; Xu E; Tenaya Therapeutics, South San Francisco, CA, USA.; Shenwai R; Tenaya Therapeutics, South San Francisco, CA, USA.; Kozubov M; Tenaya Therapeutics, South San Francisco, CA, USA.; Li C; Tenaya Therapeutics, South San Francisco, CA, USA.; Van Pell M; Tenaya Therapeutics, South San Francisco, CA, USA.; Grafton F; Tenaya Therapeutics, South San Francisco, CA, USA.; MacKay CE; Tenaya Therapeutics, South San Francisco, CA, USA.; Song X; Tenaya Therapeutics, South San Francisco, CA, USA.; Priest JR; Tenaya Therapeutics, South San Francisco, CA, USA.; Argast G; Tenaya Therapeutics, South San Francisco, CA, USA.; Mandegar MA; Tenaya Therapeutics, South San Francisco, CA, USA.; Hoey T; Tenaya Therapeutics, South San Francisco, CA, USA.; Yang J; Tenaya Therapeutics, South San Francisco, CA, USA. flairjinyang@gmail.com.
Source
Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
Subject
Language
English
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.
(© 2024. The Author(s).)
(© 2024. The Author(s).)