Suppression of class I and II histone deacetylases blunts pressure-overload cardiac hypertrophy

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Epigenetics

Background:

• Histone acetylation plays a key role in regulating gene expression within the heart.
• Histone deacetylase (HDAC) inhibitors show potential for treating hypertrophic heart disease, but their effects require further investigation in vivo.

Purpose of the Study:

• To investigate the efficacy of broad-spectrum HDAC inhibitors in a pressure-overload model of cardiac hypertrophy.
• To assess the impact of HDAC inhibition on cardiac growth, fibrosis, and function.

Main Methods:

• Utilized a physiological banding model of cardiac hypertrophy in vivo.
• Administered two broad-spectrum HDAC inhibitors at varying doses over short-term (3-week) and long-term (9-week) periods.
• Evaluated cardiac function using echocardiography and invasive pressure measurements; assessed cardiomyocyte growth, apoptosis, fibrosis, and myosin heavy chain isoform expression.

Main Results:

• Observed dose-responsive suppression of ventricular growth with well-tolerated clinical outcomes and preserved cardiac performance.
• Demonstrated blocked cardiomyocyte growth without inducing cell death or apoptosis.
• Showed diminished fibrotic changes and blocked collagen synthesis in isolated cardiac fibroblasts.
• Documented preservation of systolic function, evidenced by attenuated hypertrophy-associated myosin heavy chain isoform switching.

Conclusions:

• HDAC inhibition presents a viable therapeutic strategy for load-induced heart disease.
• The findings support the potential of HDAC inhibitors in managing cardiac hypertrophy and preserving heart function.