HDAC6型
射血分数
心力衰竭
心肌病
纤维化
心脏病学
医学
病理生理学
射血分数保留的心力衰竭
内科学
组蛋白脱乙酰基酶
组蛋白
化学
基因
生物化学
作者
Sara Ranjbarvaziri,Aliya Zeng,Iris Wu,Amara Greer-Short,Farshad Farshidfar,Ana Budan,Emma Xu,Reva Shenwai,Matthew Kozubov,Cindy Li,Malcolm Pell,Francis Grafton,Charles Mackay,Xiaomei Song,James R. Priest,Gretchen Argast,Mohammad A. Mandegar,Timothy Hoey,Jin Yang
标识
DOI:10.1038/s41467-024-45440-7
摘要
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.
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