Abstract 2950: Distinct Regulation of Cardiac Function by Histone Deacetylase Inhibitors in Response to Pressure Overload
Background- Recent work has uncovered that histone acetylation might work as a nodal control point in the complex signal network for gene regulation in hypertrophic myocardium, moreover, histone deacetylase (HDAC)inhibitors might hold promise as potential therapeutic agents in hypertrophic heart disease. In this study, we tested the effects of some HDAC inhibitors on hypertrophy and subsequent cardiac dysfunction in response to pressure overload.
Method and results- Transverse aortic constriction (TAC) operation were performed on C57BL/6J mice and pressure overload was successfully produced. Cardiac hypertrophy and dysfunction induced by TAC for 6 weeks were significantly blunted by trichostatin A (TSA) and valproic acid (VPA). In contrast, treatment by 4-Sodium phenylbutyrate (4-PBA) unexpectedly further exaggerated cardiac remodeling at week 6 compared with vehicle-treated mice, indicated by larger ratio of heart weight to body weight, bigger cross-sectional area and more enlarged left ventricle (LV) dimension. 4-PBA also led to lower ejection fraction and fractional shortening. Moreover, invasive hemodynamic measurements showed significantly higher LV end diastolic pressure (31.0 vs 15.5 mmHg, p<0.001) and lower contractivity index (120.8 vs 160.4, p<0.01) compared with vehicle-treated mice, suggesting the deterioration of diastolic and systolic function. In accordance with these data, the expressions of hypertrophic markers were further increased by 4-PBA administration. Kaplan-Meier analysis revealed significantly lower survival rate in 4-PBA-treated mice (32.7% vs 66.7%, p<0.001). Similarly, treatment with butyrate acid (BS), an analogue of 4-PBA, also achieved unbeneficial effect. All the 4 HDAC inhibitors successfully inhibited HDAC total activity in vivo and in vitro. Individual HDAC activity assay showed rather than class IIa members (HDAC 4 and 7), 4-PBA and BS predominantly inhibit class IHDACs (HDAC2 and 8), whereas VPA and TSA inhibit them all to a similar extent.
Conclusion- Together, these data suggest that 4-PBA and BS accelerate load -induced hypertrophy and cardiac dysfunction, whereas VPA and TSA hold opposing effects. The distinct regulation might be due to differential selectivity on certain HDAC subtypes.