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Updated: Jul 15, 2026
Histological Quantification of Chronic Myocardial Infarct in Rats
Published on: December 11, 2016
Inhibition of histone deacetylase on ventricular remodeling in infarcted rats
Tsung-Ming Lee1, Mei-Shu Lin, Nen-Chung Chang
1Cardiology Section, Department of Medicine, Taipei Medical University and Chi-Mei Medical Center, Taipei, Taiwan.
Insights
Histone deacetylase (HDAC) inhibitors, valproic acid and tributyrin, attenuated cardiac remodeling and improved heart function in infarcted rats. These findings suggest HDAC inhibition as a potential therapeutic target for heart failure.
Area of Science:
- Cardiovascular Biology
- Molecular Biology
- Pharmacology
Background:
- Histone deacetylase (HDAC) regulates gene expression by controlling histone acetylation.
- HDAC inhibitors have demonstrated effects on cardiomyocyte growth.
- Cardiac remodeling post-infarction is a significant clinical concern.
Purpose of the Study:
- To investigate the therapeutic potential of HDAC inhibitors in mitigating cardiac remodeling following myocardial infarction.
- To determine if valproic acid (VPA) and tributyrin attenuate ventricular hypertrophy and fibrosis in a rat model of infarction.
Main Methods:
- Male Wistar rats underwent ligation of the left anterior descending artery to induce infarction.
- Rats were treated with vehicle, VPA, tributyrin, theophylline (HDAC agonist), or combinations thereof for 4 weeks.
- Cardiac structure, myocyte size, collagen content, and cardiac function (shortening fraction) were assessed.
- Gene expression (atrial natriuretic peptide mRNA) and histone acetylation (acetyl histone H4) were analyzed.
Main Results:
- VPA and tributyrin significantly attenuated cardiomyocyte hypertrophy and collagen formation in both remote and border zones.
- Left ventricular shortening fraction was significantly improved in VPA- and tributyrin-treated groups.
- The beneficial effects of HDAC inhibitors were reversed by theophylline, confirming HDAC as the target.
- Increased atrial natriuretic peptide mRNA and acetyl histone H4 levels post-infarction were modulated by HDAC inhibition.
Conclusions:
- Inhibition of HDAC by VPA or tributyrin effectively attenuates ventricular remodeling after myocardial infarction in rats.
- HDAC inhibition demonstrates a beneficial effect on cardiac function and structure post-infarction.
- Targeting HDAC represents a promising therapeutic strategy for managing heart failure due to ischemic heart disease.
Abstract:
Histone deacetylase (HDAC) determines the acetylation status of histones and, thereby, controls the regulation of gene expression. HDAC inhibitors have been shown to inhibit cardiomyocyte growth in vitro and in vivo. We assessed whether HDAC inhibitors exert a beneficial effect on the remodeling heart in infarcted rats. At 24 h after ligation of the left anterior descending artery, male Wistar rats were randomized to vehicle, HDAC inhibitors [valproic acid (VPA) and tributyrin], an agonist of HDAC (theophylline), VPA + theophylline, or tributyrin + theophylline for 4 wk. Significant ventricular hypertrophy was detected as increased myocyte size at the border zone isolated by enzymatic dissociation after infarction. Cardiomyocyte hypertrophy and collagen formation at the remote region and border zone were significantly attenuated by VPA and tributyrin with a similar potency compared with that induced by the vehicle. Left ventricular shortening fraction was significantly higher in the VPA- and tributyrin-treated groups than in the vehicle-treated group. Increased synthesis of atrial natriuretic peptide mRNA after infarction was confirmed by RT-PCR, consistent with the results of immunohistochemistry and Western blot for acetyl histone H4. The beneficial effects of VPA and tributyrin were abolished by theophylline, implicating HDAC as the relevant target. Inhibition of HDAC by VPA or tributyrin can attenuate ventricular remodeling after infarction. This might provide a worthwhile therapeutic target.
