The roles of the COXs in normal physiology and in pathological conditions

在先前的研究（Gitlin等人，Cardiovascular Res.，73：227，2007），我们报道了考克斯-2参与腹主动脉瘤（AAA）的形成。此外，我们实验室的初步研究表明，B-抑制蛋白2介导的信号传导导致考克斯-2的诱导。在本研究中，我们继续这些研究，并调查了B-arrestin 2和考克斯-2在AAAs形成中的作用。AAA的形成涉及主动脉的异常扩张，随后是巨噬细胞浸润和血管壁的广泛重塑，随着时间的推移可能导致危及生命的AAA破裂。我们使用血管紧张素II（AngII）诱导的小鼠AAA模型来研究AAA的形成，并研究B-arrestin 2和考克斯-2在AAA诱导中的作用。我们以前证明了考克斯-2的缺乏减弱了小鼠中AAA的发生率（Gitlin等），此外，AngII诱导小鼠腹主动脉中显著的考克斯-2表达。与我们先前观察到的考克斯-2缺陷减少AAA形成相似，我们目前的研究表明，B-抑制蛋白2缺陷显著减少小鼠中AngII诱导的AAA形成。为了确定B-抑制蛋白2促进AAA形成的可能机制，我们研究了B-抑制蛋白2介导的考克斯-2、ERK 1/2激活、NF-κ B激活和STAT 3激活的诱导。因此，B-抑制蛋白2的缺乏可能通过降低B-抑制蛋白2介导的信号传导和降低活化考克斯-2介导的信号传导途径来降低AngII诱导的AAA的发生率。

In a previous study (Gitlin et al. Cardiovascular Res., 73:227, 2007), we reported the involvement of COX-2 in the formation of abdominal aortic aneurysms (AAA)s. Furthermore, preliminary studies in our laboratory have indicated that B-arrestin2-mediated signaling leads to the induction of COX-2. In the present research, we have continued these studies and investigated the roles of B-arrestin2 and COX-2 in the formation of AAAs. AAA formation involves an abnormal dilation of the aorta, followed by macrophage infiltration and extensive remodeling of the vessel wall, which with time may lead to life-threatening AAA rupture. We have used a model of angiotensin II (AngII) induced AAAs in mice to study AAA formation and investigate the roles of B-arrestin2 and COX-2 in the induction of AAAs. We previously demonstrated that the deficiency of COX-2 attenuates the incidence AAAs in mice (Gitlin et al.), and furthermore that AngII induces significant COX-2 expression in the abdominal aortae of mice. Similar to our previous observation that COX-2-deficiency reduced AAA formation, our current studies show that the deficiency of B-arrestin2 significantly reduced AngII-induced AAA formation in mice. To identify possible mechanisms by which B-arrestin2 contributes to AAA formation, we have investigated B-arrestin2-mediated induction of COX-2, ERK1/2 activation, NF-kB activation and STAT3 activation. Thus, the deficiency of B-arrestin2 may attenuate the incidence of AngII-induced AAAs by decreasing both B-arrestin2-mediated signaling and decreased activation COX-2-mediated signaling pathways.