Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287-4904, USA.
Department of Surgery, Division of Cardiac Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287-4904, USA.
J Mol Cell Cardiol. 2015 Apr;81:18-22. doi: 10.1016/j.yjmcc.2015.01.019. Epub 2015 Feb 2.
Emerging evidence strongly supports a role for HDAC2 in the transcriptional regulation of endothelial genes and vascular function. We have recently demonstrated that HDAC2 reciprocally regulates the transcription of Arginase2, which is itself a critical modulator of endothelial function via eNOS. Moreover HDAC2 levels are decreased in response to the atherogenic stimulus OxLDL via a mechanism that is apparently dependent upon proteasomal degradation. NEDDylation is a post-translational protein modification that is tightly linked to ubiquitination and thereby protein degradation. We propose that changes in NEDDylation may modulate vascular endothelial function in part through alterations in the proteasomal degradation of HDAC2. In HAEC, OxLDL exposure augmented global protein NEDDylation. Pre-incubation of mouse aortic rings with the NEDDylation activating enzyme inhibitor, MLN4924, prevented OxLDL-induced endothelial dysfunction. In HAEC, MLN enhanced HDAC2 abundance, decreased expression and activity of Arginase2, and blocked OxLDL-mediated reduction of HDAC2. Additionally, HDAC2 was shown to be a substrate for NEDD8 conjugation and this interaction was potentiated by OxLDL. Further, HDAC2 levels were reciprocally regulated by ectopic expression of NEDD8 and the de-NEDDylating enzyme SENP8. Our findings indicate that the observed improvement in endothelial dysfunction with inhibition of NEDDylation activating enzyme is likely due to an HDAC2-dependent decrease in Arginase2. NEDDylation activating enzyme may therefore be a novel target in endothelial dysfunction and atherogenesis.
越来越多的证据有力地支持了 HDAC2 在血管内皮基因转录调控和血管功能中的作用。我们最近的研究表明，HDAC2 可相互调节精氨酸酶 2 的转录，而精氨酸酶 2 本身是通过 eNOS 对内皮功能的关键调节因子。此外，HDAC2 的水平会因 OxLDL 等动脉粥样硬化刺激而降低，这种降低是通过一种显然依赖于蛋白酶体降解的机制实现的。NEDDylation 是一种翻译后蛋白修饰，与泛素化和蛋白降解紧密相关。我们提出，NEDDylation 的变化可能通过改变 HDAC2 的蛋白酶体降解来调节血管内皮功能。在 HAEC 中，OxLDL 暴露会增加整体蛋白 NEDDylation。用 NEDDylation 激活酶抑制剂 MLN4924 预处理小鼠主动脉环可防止 OxLDL 诱导的内皮功能障碍。在 HAEC 中，MLN 增强了 HDAC2 的丰度，降低了精氨酸酶 2 的表达和活性，并阻断了 OxLDL 介导的 HDAC2 减少。此外，HDAC2 是 NEDD8 缀合的底物，OxLDL 增强了这种相互作用。此外，HDAC2 的水平受到 NEDD8 异位表达和去 NEDDylating 酶 SENP8 的反向调节。我们的研究结果表明，抑制 NEDDylation 激活酶可改善内皮功能障碍，这可能是由于 HDAC2 依赖性的精氨酸酶 2 减少所致。因此，NEDDylation 激活酶可能是内皮功能障碍和动脉粥样硬化形成的一个新靶点。
