Transcriptional regulation of endothelial arginase 2 by histone deacetylase 2.
Transcriptional regulation of endothelial arginase 2 by histone deacetylase 2.
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DOI：
10.1161/atvbaha.114.303685
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发表时间：
2014-07
期刊：
影响因子：
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通讯作者：
Berkowitz D
中科院分区：
文献类型：
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作者：
Pandey D;Sikka G;Bergman Y;Kim JH;Ryoo S;Romer L;Berkowitz D
精氨酸酶2是动脉粥样硬化的关键靶点，因为它控制内皮NO、增殖、纤维化和炎症。内皮细胞中Arg2转录的调节因子尚未被表征。本研究的目的是确定特异性hdac在调节内皮细胞Arg2转录和内皮功能中的作用。HDAC抑制剂trichostatin A （TSA）增加了HAEC和小鼠主动脉环中Arg2 mRNA、蛋白和活性的水平。这些变化具有时间和剂量依赖模式，并导致arg2依赖性内皮功能障碍。TSA和致动脉粥样硬化刺激OxLDL增强了Arg2共同启动子区域的活性。用TSA抑制HDAC也能降低内皮细胞NO，而精氨酸酶抑制能减弱这种作用。非选择性I类HDAC抑制剂增强Arg2的表达，而唯一增加Arg2表达的选择性抑制剂是moceinostat （MGCD）——一种HDAC 1和2的选择性抑制剂。此外，用MGCD预孵育的小鼠主动脉环表现出功能失调的松弛。在HAEC中过表达HDAC2（而非HDAC 1、3或8）cDNA以浓度依赖性的方式抑制Arg2的表达，而敲低HDAC2的siRNA则增强Arg2的表达。染色质免疫沉淀表明HDAC2与Arg2启动子直接结合，并且HDAC2在HAEC中的过表达阻断了oxldl介导的Arg2启动子的激活。最后，HDAC2的过表达阻断了oxldl介导的血管功能障碍。HDAC2是Arg2表达、内皮NO和内皮功能的关键调节因子。过表达或激活HDAC2是治疗内皮功能障碍和动脉粥样硬化的一种新方法。
Arginase 2 is a critical target in atherosclerosis as it controls endothelial NO, proliferation, fibrosis, and inflammation. Regulators of Arg2 transcription in the endothelium have not been characterized. The goal of the current study is to determine the role of specific HDACs in the regulation of endothelial Arg2 transcription and endothelial function. The HDAC inhibitor, trichostatin A (TSA) increased levels of Arg2 mRNA, protein, and activity in both HAEC and mouse aortic rings. These changes occurred with both time- and dose-dependent patterns, and resulted in Arg2-dependent endothelial dysfunction. TSA and the atherogenic stimulus OxLDL enhanced the activity of common promoter regions of Arg2. HDAC inhibition with TSA also decreased endothelial NO and these effects were blunted by arginase inhibition. Non-selective class I HDAC inhibitors enhanced Arg2 expression, while the only selective inhibitor that increased Arg2 expression was mocetinostat (MGCD) – a selective inhibitor of HDACs 1 and 2. Additionally, mouse aortic rings pre-incubated with MGCD exhibited dysfunctional relaxation. Overexpression of HDAC2 (but not HDAC 1, 3 or 8) cDNA in HAEC suppressed Arg2 expression in a concentration-dependent manner, and siRNA knockdown of HDAC2 enhanced Arg2 expression. Chromatin immunoprecipitation indicated direct binding of HDAC2 to the Arg2 promoter, and HDAC2 overexpression in HAEC blocked OxLDL-mediated activation of the Arg2 promoter. Finally, overexpression of HDAC2 blocked OxLDL-mediated vascular dysfunction. HDAC2 is a critical regulator of Arg2 expression and thereby endothelial NO and endothelial function. Overexpression or activation of HDAC2 represents a novel therapy for endothelial dysfunction and atherosclerosis.