Histone deacetylase 8 regulates cortactin deacetylation and contraction in smooth muscle tissues
Histone deacetylase 8 regulates cortactin deacetylation and contraction in smooth muscle tissues
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DOI：
10.1152/ajpcell.00102.2014
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发表时间：
2014-08-01
影响因子：
5.5
通讯作者：
Tang, Dale D.
中科院分区：
文献类型：
--
作者：
Li, Jia;Chen, Shu;Tang, Dale D.
组蛋白脱乙酰酶(HDACs)是一类参与核小体组蛋白脱乙酰化和基因表达的酶。HDAC家族的一些成员也参与了非组蛋白脱乙酰化，它调节细胞周期控制、分化和细胞迁移。然而，HDAC在平滑肌收缩中的作用在很大程度上是未知的。在此，HDAC8定位于小鼠和人的血管平滑肌细胞的胞浆和胞核。慢病毒编码的HDAC8 shRNA敲除HDAC8可抑制乙酰胆碱对FORCE的反应。用HDAC8抑制剂XXIV(OSU-HDAC-44)处理平滑肌组织可诱导预收缩的平滑肌组织松弛。此外，Cortactin是一种肌动蛋白调节蛋白，在NIH3T3细胞迁移过程中经历去乙酰化。在这项研究中，乙酰胆碱刺激诱导了小鼠和人的平滑肌组织中皮质素的脱乙酰化，这一点通过使用乙酰化赖氨酸抗体的免疫印迹分析得到了证明。通过RNAi或用该抑制剂处理HDAC8可减弱皮质素脱乙酰化和肌动蛋白聚合，而不影响肌球蛋白的激活。此外，电荷中和皮质蛋白突变体的表达抑制了收缩和收缩激活过程中的肌动蛋白动力学。这些结果提示了一种新的调节平滑肌收缩的机制。作为对收缩刺激的反应，HDAC8可能介导皮质蛋白脱乙酰化，从而促进肌动蛋白细丝聚合和平滑肌收缩。
Histone deacetylases (HDACs) are a family of enzymes that mediate nucleosomal histone deacetylation and gene expression. Some members of the HDAC family have also been implicated in nonhistone protein deacetylation, which modulates cell-cycle control, differentiation, and cell migration. However, the role of HDACs in smooth muscle contraction is largely unknown. Here, HDAC8 was localized both in the cytoplasm and the nucleus of mouse and human smooth muscle cells. Knockdown of HDAC8 by lentivirus-encoding HDAC8 shRNA inhibited force development in response to acetylcholine. Treatment of smooth muscle tissues with HDAC8 inhibitor XXIV (OSU-HDAC-44) induced relaxation of precontracted smooth muscle tissues. In addition, cortactin is an actin-regulatory protein that undergoes deacetylation during migration of NIH 3T3 cells. In this study, acetylcholine stimulation induced cortactin deacetylation in mouse and human smooth muscle tissues, as evidenced by immunoblot analysis using antibody against acetylated lysine. Knockdown of HDAC8 by RNAi or treatment with the inhibitor attenuated cortactin deacetylation and actin polymerization without affecting myosin activation. Furthermore, expression of a charge-neutralizing cortactin mutant inhibited contraction and actin dynamics during contractile activation. These results suggest a novel mechanism for the regulation of smooth muscle contraction. In response to contractile stimulation, HDAC8 may mediate cortactin deacetylation, which subsequently promotes actin filament polymerization and smooth muscle contraction.