组蛋白去乙酰化酶 6 的药理学抑制可减轻凝血酶诱导的内皮屏障功能障碍。
Pharmacological inhibition of HDAC6 attenuates endothelial barrier dysfunction induced by thrombin.
机构信息
Department of Medicine, Tulane Medical School, New Orleans, LA, USA.
出版信息
Biochem Biophys Res Commun. 2011 May 20;408(4):630-4. doi: 10.1016/j.bbrc.2011.04.075. Epub 2011 Apr 21.
Abstract
BACKGROUND
Endothelial barrier dysfunction (EBD) involves microtubule disassembly and enhanced cell contractility. Histone deacetylase 6 (HDAC6) deacetylates α-tubulin, and thereby destabilizes microtubules. This study investigates a role for HDAC6 in EBD.
METHODS
EBD was induced with thrombin±HDAC6 inhibitors (tubacin and MC1575), and assessed by transendothelial electrical resistance (TEER). Markers for microtubule disassembly (α-tubulin and acetylated α-tubulin) and contraction (phosphorylated myosin light chain 2, P-MLC2) were measured using immunoblots and immunofluorescence.
RESULTS AND CONCLUSION
Thrombin induced a ∼50% decrease in TEER that was abrogated by the HDAC6 inhibitors. Moreover, inhibition of HDAC6 diminished edema in the lung injured by lipopolysaccharide. Lastly, inhibition of HDAC6 attenuated thrombin-induced microtubule disassembly and P-MLC2. Our results suggest that HDAC6 can be targeted to limit EBD.
摘要
背景
血管内皮屏障功能障碍（EBD）涉及微管解聚和增强的细胞收缩性。组蛋白去乙酰化酶 6（HDAC6）使α-微管蛋白去乙酰化，从而使微管不稳定。本研究探讨了 HDAC6 在 EBD 中的作用。
方法
用凝血酶±HDAC6 抑制剂（tubacin 和 MC1575）诱导 EBD，并通过跨内皮电阻（TEER）进行评估。使用免疫印迹和免疫荧光法测量微管解聚（α-微管蛋白和乙酰化α-微管蛋白）和收缩（磷酸化肌球蛋白轻链 2，P-MLC2）的标志物。
结果和结论
凝血酶诱导 TEER 降低约 50%，HDAC6 抑制剂可阻断该作用。此外，抑制 HDAC6 可减轻脂多糖损伤的肺组织水肿。最后，抑制 HDAC6 可减轻凝血酶诱导的微管解聚和 P-MLC2。我们的结果表明，HDAC6 可以作为靶点来限制 EBD。
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