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Published on: August 6, 2020
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Histone Deacetylase 6 Inhibitor JS28 Prevents Pathological Gene Expression in Cardiac Myocytes
Vivien Ngo1, Bernd K Fleischmann2, Manfred Jung3
1Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine University of Freiburg Germany.
Journal of the American Heart Association
|June 14, 2022
Summary
The histone deacetylase 6 (HDAC6) inhibitor JS28 effectively prevents pathological gene expression in cardiac cells with minimal impact on normal gene function, offering a promising heart failure treatment strategy.
Area of Science:
- Cardiovascular Biology
- Epigenetics
- Drug Discovery
Background:
- Epigenetic modulators are potential therapeutic targets for heart failure.
- Adverse cardiac remodeling in heart failure involves pathological gene expression.
- Histone deacetylase 6 (HDAC6) is a key epigenetic enzyme.
Purpose of the Study:
- To evaluate four epigenetic drugs, including HDAC6 inhibitor JS28, for preventing endothelin-1 induced pathological gene expression in cardiac myocytes.
- To analyze the chromatin binding profiles of the targeted epigenetic regulators.
Main Methods:
- Cardiac myocytes were differentiated and treated with endothelin-1 to induce pathological gene expression.
- The effects of bromosporine (pan-bromodomain inhibitor), JQ1 (BET inhibitor), suberoylanilide hydroxamic acid (HDAC inhibitor), and JS28 (HDAC6 inhibitor) were assessed.
- Genome-wide chromatin binding profiles of HDAC6 and BRD4 were analyzed.
Main Results:
- All four epigenetic inhibitors partially prevented endothelin-1 induced pathological gene expression.
- JS28 showed the least adverse effects on physiological gene expression compared to other inhibitors.
- HDAC6 preferentially binds to promoters of RNA processing genes, while BRD4 binds to cardiac function genes at enhancers and introns.
Conclusions:
- The HDAC6 inhibitor JS28 effectively prevents adverse gene expression changes in cardiac myocytes induced by endothelin-1.
- JS28 exhibits minimal impact on physiological gene expression, suggesting a favorable therapeutic window.
- Selective HDAC6 inhibition represents a promising strategy for heart failure treatment, warranting further in vivo and clinical investigation.
Keywords:
bromodomain‐containing proteincardiac myocyteepigeneticsheartheart failurehistone deacetylaseMore Related Videos
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