Department of Cardiovascular Surgery, Fuwai Central China Cardiovascular Hospital, The People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, P.R. China.
J Cardiovasc Pharmacol. 2022 Jun 1;79(6):815-826. doi: 10.1097/FJC.0000000000001260.
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.
组蛋白去乙酰化酶 (HDAC) 决定组蛋白的乙酰化状态，从而调节基因表达。HDAC 抑制剂已被证明可在体外和体内抑制心肌细胞生长。我们在此评估 HDAC1 是否对冠心病 (CHD) 产生加重作用。表观遗传学探针阵列显示，CHD 患者的 HDAC1 表达过度。随后，下调大鼠心肌细胞中的 HDAC1，并进行 microRNA 微阵列分析以检测 HDAC1 的下游靶标，随后进行染色质免疫沉淀验证。HDAC1 通过去乙酰化抑制 miR-182 的表达。CHD 患者的 miR-182 表达水平较低。通过酶联免疫吸附测定、逆转录定量聚合酶链反应、苏木精-伊红染色、末端脱氧核苷酸转移酶 (TdT)-介导的 2'-脱氧尿苷 5'-三磷酸 (dUTP) 缺口末端标记测定和免疫组织化学，我们观察到 HDAC1 下调可促进心脏功能、恢复脂质水平、减少心肌损伤标志物和炎症因子，并减轻 CHD 大鼠的心肌组织损伤和凋亡。相比之下，在存在 HDAC1 敲低的情况下，miR-182 下调加剧了大鼠的损伤。京都基因与基因组百科全书通路分析显示，miR-182 的靶基因主要富集在转化生长因子 (TGF)-β/Smad 通路中。Western blot 也验证了 HDAC1/miR-182 调节 TGF-β/Smad 通路活性。我们的结果表明，HDAC1 抑制 miR-182 并激活 TGF-β/Smad 通路以促进 CHD。
