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Updated: Sep 3, 2025
08:29
Assessment of Myofilament Ca2+ Sensitivity Underlying Cardiac Excitation-contraction Coupling
Published on: August 1, 2016
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HDAC Inhibition Regulates Cardiac Function by Increasing Myofilament Calcium Sensitivity and Decreasing Diastolic
Deborah M Eaton1,2, Thomas G Martin3, Michael Kasa4
1Cardiovascular Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
Pharmaceutics
|July 27, 2022
Summary
The pan-histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) improves heart failure with preserved ejection fraction (HFpEF) by enhancing cardiomyocyte contractility and myofilament function. SAHA treatment increases calcium sensitivity and reduces diastolic tension, offering a potential therapeutic strategy.
Area of Science:
- Cardiology
- Molecular Biology
- Pharmacology
Background:
- Heart failure with preserved ejection fraction (HFpEF) presents significant clinical challenges.
- Existing treatments for HFpEF have limited efficacy.
- A large animal model mimicking HFpEF was established to investigate therapeutic interventions.
Purpose of the Study:
- To elucidate the cellular and molecular mechanisms by which suberoylanilide hydroxamic acid (SAHA) modulates cardiac function in HFpEF.
- To evaluate the direct effects of SAHA on cardiomyocyte and myofilament performance.
Main Methods:
- Isolated adult feline ventricular cardiomyocytes (AFVM) and human left ventricle (LV) trabeculae were treated with SAHA or vehicle.
- Functional data, including contractility and relaxation, were recorded.
- Skinned myocytes were used to assess myofilament calcium sensitivity and passive stiffness.
- Mass spectrometry identified protein modifications induced by SAHA.
Main Results:
- SAHA treatment increased contractility and improved relaxation in AFVM without altering peak calcium transients.
- SAHA enhanced myofilament calcium sensitivity and reduced passive stiffness in both feline and human cardiac tissues.
- Mass spectrometry revealed increased acetylation of the myosin regulatory light chain.
- SAHA reduced diastolic tension and increased developed force in human trabeculae.
Conclusions:
- SAHA directly improves cardiac function at the cardiomyocyte and myofilament level.
- Increased myofilament calcium sensitivity and reduced diastolic tension are key mechanisms of SAHA's beneficial effects.
- SAHA demonstrates therapeutic potential for HFpEF by targeting fundamental contractile dysfunctions.
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