S-adenosylhomocysteine induces inflammation through NFkB: A possible role for EZH2 in endothelial cell activation.
S-adenosylhomocysteine induces inflammation through NFkB: A possible role for EZH2 in endothelial cell activation.
复制标题
DOI：
10.1016/j.bbadis.2015.10.019
复制
发表时间：
2016-01
期刊：
影响因子：
--
通讯作者：
Handy DE
中科院分区：
文献类型：
--
作者：
Barroso M;Kao D;Blom HJ;Tavares de Almeida I;Castro R;Loscalzo J;Handy DE
S-同型半胱氨酸腺苷可诱导血管内皮细胞功能障碍和活化，促进动脉粥样硬化的形成，但其在炎症介质NFkB活化中的作用尚不清楚。我们的目的是确定NFkB在SAH诱导的内皮细胞激活中的作用。此外，我们研究了SAH作为S腺苷蛋氨酸依赖的甲基转移酶的有效抑制剂是否抑制了EZH2甲基转移酶的功能，从而促进了SAH诱导的内皮细胞的激活。我们发现过量的SAH增加了人冠状动脉内皮细胞黏附分子和细胞因子的表达。重要的是，这种上调在表达显性阴性形式的NFkB抑制剂IKB的细胞中被抑制。此外，SAH的积累触发了规范和非规范NFkB通路的激活，降低了EZH2，并减少了组蛋白3赖氨酸27的三甲基化。EZH2基因敲除概括了过量SAH对内皮细胞激活的影响，即它诱导了NFkB的激活以及随后黏附分子和细胞因子的上调。我们的发现表明，过量的SAH抑制表观遗传调节因子EZH2可能有助于NFkB的激活和随之而来的血管炎症反应。这些研究揭示了SAH调节的新靶点，表明SAH积聚介导的EZH2抑制和NFkB激活可能有助于其在血管系统中的不利影响。
S-Adenosylhomocysteine (SAH) can induce endothelial dysfunction and activation, contributing to atherogenesis; however, its role in the activation of the inflammatory mediator NFkB has not been explored. Our aim was to determine the role of NFkB in SAH-induced activation of endothelial cells. Furthermore, we examined whether SAH, as a potent inhibitor of S-adenosylmethionine-dependent methyltransferases, suppresses the function of EZH2 methyltransferase to contribute to SAH-induced endothelial cell activation. We found that excess SAH increases the expression of adhesion molecules and cytokines in human coronary artery endothelial cells. Importantly, this up-regulation was suppressed in cells expressing a dominant negative form of the NFkB inhibitor, IkB. Moreover, SAH accumulation triggers the activation of both the canonical and non-canonical NFkB pathways, decreases EZH2, and reduces histone 3 lysine 27 trimethylation. EZH2 knockdown recapitulated the effects of excess SAH on endothelial activation, i.e., it induced NFkB activation and the subsequent up-regulation of adhesion molecules and cytokines. Our findings suggest that suppression of the epigenetic regulator EZH2 by excess SAH may contribute to NFkB activation and the consequent vascular inflammatory response. These studies unveil new targets of SAH regulation, demonstrating that EZH2 suppression and NFkB activation mediated by SAH accumulation may contribute to its adverse effects in the vasculature.