促炎细胞因子
基质金属蛋白酶
肿瘤坏死因子α
癌症研究
AP-1转录因子
发病机制
生物
免疫学
炎症
医学
转录因子
生物化学
基因
作者
Lei Bai,Lijuan Ge,Bin Zhang,Yujing Zhang,Junjie Gu,Li Liu,Song Ye
标识
DOI:10.1016/j.yexcr.2022.113386
摘要
Abdominal aortic aneurysm (AAA) is a life-threatening disorder that occurs in the aorta. The inflammatory thickness of the aneurysm wall and perianeurysmal fibrosis are two main causes of AAA pathogenesis; however, the molecular mechanisms involved in these two processes are still unclear. We discovered that C-terminal binding protein 1 (CtBP1) and CtBP2 were overexpressed in the aortas of AAA-model mice created by treatment with CaCl2 and elastase. Molecular analyses revealed that the CtBP heterodimer couples with histone acetyltransferase p300 and transcription factor AP1 (activator protein 1) to transactivate a set of matrix metalloproteinases (MMPs, including MMP1a, 3, 7, 9, and 12) and proinflammatory cytokines, including interleukin-1 β (IL-1β), IL-6, and tumor necrosis factor-alpha (TNF-α). Knockdown of CtBPs or AP1 subunits or blockage of CtBPs with specific small molecule inhibitors significantly suppressed the in vitro expression of MMPs and proinflammatory cytokines. The administration of CtBP inhibitors in AAA-model mice also inhibited MMPs and proinflammatory cytokines, thereby improving the AAA outcome. Taken together, our results revealed a new regulatory mechanism involving MMPs and proinflammatory cytokines in the pathogenesis of AAA. This discovery suggests that targeting CtBPs may be a therapeutic strategy for AAA by attenuating the inflammatory response and matrix destruction.
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