HDAC6 is associated with the formation of aortic dissection in human
HDAC6 is associated with the formation of aortic dissection in human
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HDAC6 与人类主动脉夹层的形成相关
DOI：
10.1186/s10020-019-0080-7
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发表时间：
2019-03-29
影响因子：
5.7
通讯作者：
Jiang, Ding-Sheng
中科院分区：
文献类型：
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作者：
Guo, Xian;Fang, Ze-Min;Jiang, Ding-Sheng
背景主动脉夹层（AD）的病理特征包括血管平滑肌细胞（VSMC）损失、弹性纤维分数和主动脉炎症反应。然而，人们对这些生物学过程的翻译后修饰机制知之甚少。方法从36例冠状动脉疾病（CAD，作为对照）患者和36例A型AD（TAAD）患者中收集72份主动脉样本，用于蛋白质检测。采用染色质免疫沉淀（ChIP）-PCR鉴定H3K23ac调控的基因，并利用HDAC6抑制剂图巴他汀A阐明HDAC6调控的下游机制。结果发现TAAD患者主动脉中组蛋白脱乙酰酶HDAC6蛋白水平降低，H4K12ac、H3K23ac蛋白水平显着升高，而与 CAD 患者相比，H3K18ac、H4K8ac 和 H4K5ac 显着下降。尽管用 HDAC6 抑制剂图巴他汀 A 治疗后，人 VSMC 中的 H3K23ac、H3K18ac 和 H4K8ac 有所增加，但只有 H3K23ac 在人体组织中显示出相同的结果。值得注意的是，ChIP-PCR的结果表明，在TAAD患者的主动脉样本中，H3K23ac富含细胞外基质（ECM）相关基因，包括Col1A2、Col3A1、CTGF、POSTN、MMP2、TIMP2和ACTA2。此外，我们的结果表明，HDAC6在TAAD的病理过程中调节H4K20me2和p-MEK1/2。结论这些结果表明HDAC6通过调节H3K23ac、H4K20me2和p-MEK1/2参与人类TAAD的形成，从而为靶向蛋白质翻译后修饰（PTM）（主要是组蛋白PTM）治疗TAAD提供了策略。
BackgroundThe pathological features of aortic dissection (AD) include vascular smooth muscle cell (VSMC) loss, elastic fiber fraction, and inflammatory responses in the aorta. However, little is known about the post-translational modification mechanisms responsible for these biological processes.MethodsA total of 72 aorta samples, used for protein detection, were collected from 36 coronary artery disease (CAD, served as the control) patients and 36 type A AD (TAAD) patients. Chromatin immunoprecipitation (ChIP)-PCR was used to identify the genes regulated by H3K23ac, and tubastatin A, an inhibitor of HDAC6, was utilized to clarify the downstream mechanisms regulated by HDAC6.ResultsWe found that the protein level of histone deacetylase HDAC6 was reduced in the aortas of patients suffering from TAAD and that the protein levels of H4K12ac, and H3K23ac significantly increased, while H3K18ac, H4K8ac, and H4K5ac dramatically decreased when compared with CAD patients. Although H3K23ac, H3K18ac, and H4K8ac increased in the human VSMCs after treatment with the HDAC6 inhibitor tubastatin A, only H3K23ac showed the same results in human tissues. Notably, the results of ChIP-PCR demonstrated that H3K23ac was enriched in extracellular matrix (ECM)-related genes, including Col1A2, Col3A1, CTGF, POSTN, MMP2, TIMP2, and ACTA2, in the aortic samples of TAAD patients. In addition, our results showed that HDAC6 regulates H4K20me2 and p-MEK1/2 in the pathological process of TAAD.ConclusionsThese results indicate that HDAC6 is involved in human TAAD formation by regulating H3K23ac, H4K20me2 and p-MEK1/2, thus, providing a strategy for the treatment of TAAD by targeting protein post-translational modifications (PTMs), chiefly histone PTMs.