HDAC9 Complex Inhibition Improves Smooth Muscle Dependent Arterial Stenosis

Patients with heterozygous missense mutations in the ACTA2 or MYH11 genes are known to exhibit thoracic aortic aneurysm (TAA) and a risk of early onset aortic dissection. However, less common phenotypes involving arterial obstruction are also observed, including coronary and cerebrovascular stenotic disease. Recently an epigenetic complex containing the histone deacetylase HDAC9 and the long noncoding RNA, MALAT1 was implicated in pathologic vascular smooth muscle cell phenotypic changes in aneurysmal disease, however its involvement in stenotic disease has not been explored. Herein we implicate the HDAC9-MALAT1 complex in transcriptional silencing of contractile associated gene products, known to undergo downregulation in stenotic lesions. Furthermore, neointimal formation was inhibited in Hdac9 or Malat1 deficient mice with preservation of contractile protein expression. Pharmacologic targeting of the complex through either MALAT1 antisense oligonucleotides or inhibition of the methyltransferase EZH2 reduced neointimal formation. In conclusion, we report the implication of the HDAC9-MALAT1 complex in stenotic disease and demonstrate that pharmacologic therapy based on epigenetic targets can ameliorate arterial obstruction in an experimental system. ChipSep analysis of ACTA2 mutants versus wild type human smooth muscle cells.

已知携带ACTA2或MYH11基因杂合错义突变的患者会表现为胸主动脉瘤（thoracic aortic aneurysm, TAA），且存在早发性主动脉夹层的风险。不过临床中也观察到累及动脉阻塞的少见表型，包括冠状动脉及脑血管狭窄性疾病。近期有研究证实，包含组蛋白去乙酰化酶HDAC9（histone deacetylase HDAC9）与长链非编码RNA MALAT1（long noncoding RNA MALAT1）的表观遗传复合物，参与动脉瘤疾病中病理性血管平滑肌细胞的表型改变，但其在狭窄性疾病中的作用尚未被探究。本研究发现，HDAC9-MALAT1复合物可介导收缩相关基因产物的转录沉默——这类基因产物在狭窄病变中会出现表达下调。此外，在Hdac9或Malat1基因缺陷小鼠中，新内膜形成受到显著抑制，且收缩蛋白的表达得以保留。通过MALAT1反义寡核苷酸或抑制甲基转移酶EZH2（methyltransferase EZH2）靶向干预该复合物，均可有效减少新内膜的形成。综上，本研究明确了HDAC9-MALAT1复合物在狭窄性疾病中的作用，并证实基于表观遗传靶点的药物治疗可在实验体系中改善动脉阻塞症状。本研究还对ACTA2突变型与野生型人平滑肌细胞开展了ChipSep分析。