Abstract 354: Acetylation Regulates miR-133a Expression In Cardiac Hypertrophy
Background: The expression level of several microRNAs (miRNAs) is affected by pressure overload hypertrophy and has an impact on cardiac function. Histone deacetylases (HDACs) regulate the transcription of many genes whose expression is altered in hypertrophy. Therefore, we hypothesize that acetylation regulates the expression of some miRs during cardiac hypertrophy.
Methods: Transverse aortic constriction (TAC) was performed to initiate cardiac hypertrophy induced by pressure overload. Mice were treated with the Class I and IIb HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) in the drinking water post-TAC for 2 and 4 weeks. miRNAs expression normalized to RNU6B was determined by qRT-PCR. Echocardiography was performed at baseline and post-TAC endpoints to assess physiological parameters. Chromatin immunoprecipitation (ChIP) was used to identify HDACs and transcription factors associated with miR-133a promoter.
Results: Based on previous studies, we selected 8 miRNAs that play major roles in hypertrophy and assessed the effect of SAHA treatment on their expression level. The expression of one of the miRNAs, miR-133a was significantly (P < 0.05) downregulated at both 2 weeks (1887 ±105, n=8) and 4 weeks post-TAC (1651 ±103, n=9) compared to control group (2972 ±334, n=11). SAHA treatment significantly de-repressed miR-133a expression 2 weeks post-TAC (3317 ±560, n=12) and to a lesser extent after 4 weeks post-TAC (2391 ±455, n=10). As expected, left atrium (LA) diameter, a marker of diastolic pressure, increased 2 weeks post-TAC, while SAHA treatment significantly reduced LA diameter. miR-133a targets connective tissue growth factor (CTGF) and collagen 1a1. Consistent with SAHA-mediated miR-133a de-repression, CTGF expression and collagen volume fraction were decreased compared to TAC alone. Importantly, ChIP analysis revealed that HDAC2 was present on the miR-133a promoter.
Conclusion: We show that HDAC2, a Class I HDAC, plays a role in the regulation of miR-133a expression in cardiac hypertrophy. HDACs and miRNAs are key regulators of the events mediating cardiac pathology. Our work demonstrates that HDAC inhibition may be an attractive therapeutic strategy for the regulation of some miRNAs in heart disease.
- © 2013 by American Heart Association, Inc.