Abstract 19684: The Deficiency of β-Arrestin 2 Attenuates Abdominal Aortic Aneurysm Formation in Mice
β-arrestin 2 (βarr2 ) is a multifunctional scaffolding protein that participates in the regulation of numerous signaling pathways by coupling with G-protein coupled receptors, such as the angiotensin II (AngII) receptor AT1a. The aim of the current study was to examine the role βarr2 in AngII-induced abdominal aortic aneurysm (AAA) formation in mice. Male Apoe-/-/βarr2+/+ and Apoe-/-/βarr2-/- mice were infused with AngII (1000 ng/kg/day) or saline (vehicle) for 28 days and analyzed for AAA incidence and severity. AngII induced a 61.8% incidence (21 of 34) of AAAs in Apoe-/-/βarr2+/+ mice, as compared to 9.5% (2 of 21) in Apoe-/-/βarr2-/- mice, indicating the importance of βarr2 in AAA formation. To investigate the mechanisms by which βarr2 contributes to AAAs, we determined the effect of βarr2 deficiency on the expression of the inflammatory mediator cyclooxygenase 2 (COX-2) that we have previously shown to be a key contributor to AngII-induced AAA pathology. AngII induced abundant COX-2 expression in the abdominal aortas of Apoe-/-/βarr2+/+ mice, whereas COX-2 expression was significantly attenuated in the aortas of Apoe-/-/βarr2-/- mice (P<0.05), indicating that βarr2 is involved in the induction of COX-2 in response to AngII. An extensively studied pathway triggered by the βarr2-AT1a complex is ERK1/2 activation, and pERK1/2-mediated signaling has been independently shown to be important in AAA development. Indeed, activated ERK1/2 was observed in the abdominal aortas of Apoe-/-/βarr2+/+ mice, but not in the abdominal aortas of Apoe-/-/βarr2-/- mice. To determine if ERK1/2 activation was a mechanism for βarr2-AT1a-induced COX-2 expression, Apoe-/-/βarr2+/+ mice were treated with the ERK1/2 inhibitor, CI1040 (100mg/kg), together with AngII and examined for COX-2 expression. ERK1/2 inhibition markedly decreased AngII-induced COX-2 expression in the abdominal aortas of Apoe-/-/βarr2+/+ mice (P<0.05) to a level that was equivalent to the COX-2 expression observed in Apoe-/-/βarr2-/- mice. Thus, βarr2 may contribute to AAA formation by activating the ERK1/2-COX-2 pathway. These studies have important implications for the design of therapeutics that target βarr2-mediated signaling for the treatment of AAAs.
- © 2012 by American Heart Association, Inc.