Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, Australia.
Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China.
Clin Sci (Lond). 2020 May 15;134(9):1049-1061. doi: 10.1042/CS20191020.
Abdominal aortic aneurysm (AAA) is an important cause of mortality in older adults. Chronic inflammation and excessive matrix remodelling are considered important in AAA pathogenesis. Kinins are bioactive peptides important in regulating inflammation. Stimulation of the kinin B2 receptor has been previously reported to promote AAA development and rupture in a mouse model. The endogenous B2 receptor agonist, bradykinin, is generated from the kallikrein-kinin system following activation of plasma kallikrein by Factor XII (FXII). In the current study whole-body FXII deletion, or neutralisation of activated FXII (FXIIa), inhibited expansion of the suprarenal aorta (SRA) of apolipoprotein E-deficient mice in response to angiotensin II (AngII) infusion. FXII deficiency or FXIIa neutralisation led to decreased aortic tumor necrosis factor-α-converting enzyme (TACE/a disintegrin and metalloproteinase-17 (aka tumor necrosis factor-α-converting enzyme) (ADAM-17)) activity, plasma kallikrein concentration, and epithelial growth factor receptor (EGFR) phosphorylation compared with controls. FXII deficiency or neutralisation also reduced Akt1 and Erk1/2 phosphorylation and decreased expression and levels of active matrix metalloproteinase (Mmp)-2 and Mmp-9. The findings suggest that FXII, kallikrein, ADAM-17, and EGFR are important molecular mediators by which AngII induces aneurysm in apolipoprotein E-deficient mice. This could be a novel pathway to target in the design of drugs to limit AAA progression.
腹主动脉瘤（AAA）是老年人死亡的一个重要原因。慢性炎症和过度的基质重塑被认为在 AAA 的发病机制中很重要。激肽是调节炎症的重要生物活性肽。先前的研究表明，激肽 B2 受体的刺激可促进小鼠模型中 AAA 的发展和破裂。内源性 B2 受体激动剂缓激肽在血浆激肽原被 XII 因子（FXII）激活后，从激肽释放酶-激肽系统中产生。在本研究中，全身性 FXII 缺失或激活的 FXII（FXIIa）中和，抑制了载脂蛋白 E 缺陷型小鼠对血管紧张素 II（AngII）输注的肾上主动脉（SRA）扩张。FXII 缺乏或 FXIIa 中和导致与对照组相比，主动脉肿瘤坏死因子-α转换酶（TACE/a 分解素和金属蛋白酶-17（又称肿瘤坏死因子-α转换酶）（ADAM-17））活性、血浆激肽原浓度和表皮生长因子受体（EGFR）磷酸化降低。FXII 缺乏或中和还降低了 Akt1 和 Erk1/2 磷酸化，并减少了活性基质金属蛋白酶（Mmp）-2 和 Mmp-9 的表达和水平。这些发现表明，FXII、激肽、ADAM-17 和 EGFR 是 AngII 诱导载脂蛋白 E 缺陷型小鼠发生动脉瘤的重要分子介质。这可能是设计限制 AAA 进展的药物的新途径。
