Histone Deacetylase 1 Depletion Alleviates Coronary Heart Disease Via the MicroRNA-182-Mediated Transforming Growth Factor β/Smad Signaling Pathway.

Abstract

Histone deacetylase (HDAC) determines the acetylation status of histones, thereby regulating gene expression. HDAC inhibitors have been demonstrated to suppress cardiomyocyte growth in vitro and in vivo. We assessed here whether HDAC1 exerts an aggravating effect on coronary heart disease (CHD). Epigenetic probe array revealed that HDAC1 was overexpressed in patients with CHD. HDAC1 was then downregulated in rat cardiomyocytes, and microRNA microarray analysis was performed to detect downstream targets of HDAC1, followed by chromatin immunoprecipitation validation. HDAC1 inhibited miR-182 expression through deacetylation. miR-182 was poorly expressed in patients with CHD. Using enzyme-linked immunosorbent assay, Reverse transcription-quantitative PCR, hematoxylin-eosin staining, terminal deoxynucleotidyl transferase (TdT)-mediated 2'-deoxyuridine 5'-triphosphate (dUTP) nick-end labeling assay, and immunohistochemistry, we observed that HDAC1 downregulation promoted cardiac function, restored lipid levels, reduced myocardial injury markers and inflammatory factors, and alleviated myocardial tissue damage and apoptosis in CHD rats. By contrast, miR-182 downregulation exacerbated injury in rats in the presence of HDAC1 knockdown. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the target genes of miR-182 were mainly enriched in the transforming growth factor (TGF)-β/Smad pathway. Western blot also validated that HDAC1/miR-182 modulated the TGF-β/Smad pathway activity. Our results demonstrated that HDAC1 repressed miR-182 and activated the TGF-β/Smad pathway to promote CHD.