HDAC9 complex inhibition improves smooth muscle-dependent stenotic vascular disease
HDAC9 complex inhibition improves smooth muscle-dependent stenotic vascular disease
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DOI：
10.1172/jci.insight.124706
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发表时间：
2019-01-24
期刊：
影响因子：
8
通讯作者：
Lindsay, Mark E.
中科院分区：
文献类型：
--
作者：
Cardenas, Christian L. Lino;Kessinger, Chase W.;Lindsay, Mark E.
已知ACTA 2或MYH 11基因杂合错义突变的患者表现出胸主动脉瘤和早发性主动脉夹层的风险。然而，也观察到涉及动脉阻塞的不太常见的表型，包括冠状动脉和脑血管狭窄疾病。在此，我们暗示HDAC9复合物在收缩蛋白相关基因的转录沉默中，已知在狭窄病变中经历下调。此外，在HDAC9或MALAT1缺陷小鼠中抑制了新生内膜形成，并保留了收缩蛋白的表达。通过MALAT 1反义寡核苷酸或抑制甲基转移酶EZH 2（HDAC 9复合物募集的催化介质）对HDAC 9复合物进行药理靶向，减少新生内膜形成。总之，我们报告了HDAC9复合物在狭窄性疾病中的意义，并证明了靶向表观遗传复合物的药物治疗可以改善实验系统中的动脉阻塞。
Patients with heterozygous missense mutations in the ACTA2 or MYH11 gene are known to exhibit thoracic aortic aneurysm and a risk of early-onset aortic dissection. However, less common phenotypes involving arterial obstruction are also observed, including coronary and cerebrovascular stenotic disease. Herein we implicate the HDAC9 complex in transcriptional silencing of contractile protein-associated genes, 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 HDAC9 complex through either MALAT1 antisense oligonucleotides or inhibition of the methyltransferase EZH2 (catalytic mediator recruited by the HDAC9 complex) reduced neointimal formation. In conclusion, we report the implication of the HDAC9 complex in stenotic disease and demonstrate that pharmacologic therapy targeting epigenetic complexes can ameliorate arterial obstruction in an experimental system.