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

在之前的一项研究中（Gitlin等人）。心血管杂志，73:227,2007)，我们报道了COX-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 -arrestin2介导的信号传导导致COX-2的诱导。在本研究中，我们继续这些研究，并研究了B-arrestin2和COX-2在AAAs形成中的作用。AAA的形成包括主动脉异常扩张，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。我们利用血管紧张素II （AngII）诱导的小鼠AAAs模型来研究AAA的形成，并探讨B-arrestin2和COX-2在AAAs诱导中的作用。我们之前证明COX-2的缺乏会降低小鼠AAAs的发生率（Gitlin等人），此外，AngII诱导小鼠腹主动脉中COX-2的显著表达。与我们之前观察到的cox -2缺乏减少AAA的形成类似，我们目前的研究表明，B-arrestin2缺乏显著减少了小鼠血管i诱导的AAA的形成。为了确定B-arrestin2促进AAA形成的可能机制，我们研究了B-arrestin2介导的COX-2、ERK1/2激活、NF-kB激活和STAT3激活的诱导。因此，B-arrestin2的缺乏可能通过降低B-arrestin2介导的信号通路和降低cox -2介导的信号通路的激活来减弱血管内皮细胞诱导的AAAs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.