Key result
HDAC inhibition preserves miR-133a expression and attenuates cardiac fibrosis after transverse aortic constriction.
Why the study?
The transcriptional regulation of miRNAs, including miR-133a, by HDACs during cardiac hypertrophy is poorly understood.
Does class I and IIb HDAC inhibition prevent miR-133a downregulation and cardiac fibrosis in CD1 mice with pressure overload hypertrophy?
Does class I and IIb HDAC inhibition prevent miR-133a downregulation and cardiac fibrosis in CD1 mice with pressure overload hypertrophy?
p-value: p=<0.05
HDACs regulate pressure overload-induced miR-133a downregulation, and their inhibition reduces cardiac fibrosis and improves diastolic function markers in a mouse model.
HDAC inhibition may preserve miR-133a and limit fibrosis in murine pressure overload; hypothesis-generating for human diastolic HF trials.
BACKGROUND: MicroRNAs (miRNAs) and histone deacetylases (HDACs) serve a significant role in the pathogenesis of a variety of cardiovascular diseases. The transcriptional regulation of miRNAs is poorly understood in cardiac hypertrophy. We investigated whether the expression of miR-133a is epigenetically regulated by class I and IIb HDACs during hypertrophic remodeling. METHODS AND RESULTS: Transverse aortic constriction (TAC) was performed in CD1 mice to induce pressure overload hypertrophy. Mice were treated with class I and IIb HDAC inhibitor (HDACi) via drinking water for 2 and 4 weeks post TAC. miRNA expression was determined by real-time polymerase chain reaction. Echocardiography was performed at baseline and post TAC end points for structural and functional assessment. Chromatin immunoprecipitation was used to identify HDACs and transcription factors associated with miR-133a promoter. miR-133a expression was downregulated by 0.7- and 0.5-fold at 2 and 4 weeks post TAC, respectively, when compared with vehicle control (P<0.05). HDAC inhibition prevented this significant decrease 2 weeks post TAC and maintained miR-133a expression near vehicle control levels, which coincided with (1) a decrease in connective tissue growth factor expression, (2) a reduction in cardiac fibrosis and left atrium diameter (marker of end-diastolic pressure), suggesting an improvement in diastolic function. Chromatin immunoprecipitation analysis revealed that HDAC1 and HDAC2 are present on the miR-133a enhancer regions. CONCLUSIONS: The results reveal that HDACs play a role in the regulation of pressure overload-induced miR-133a downregulation. This work is the first to provide insight into an epigenetic-miRNA regulatory pathway in pressure overload-induced cardiac fibrosis.
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Renaud et al. (2015) studied Pressure overload-induced cardiac fibrosis and hypertrophy. Class I and IIb HDAC inhibitor (HDACi) vs. Vehicle control was evaluated on miR-133a expression (p=<0.05). HDAC inhibition prevented the significant decrease in miR-133a expression 2 weeks post transverse aortic constriction compared to vehicle control (P<0.05), reducing cardiac fibrosis.
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