β-Arrestin-2 Deficiency Attenuates Abdominal Aortic Aneurysm Formation in Mice

Rationale: Abdominal aortic aneurysms (AAAs) are a chronic inflammatory vascular disease for which pharmacological treatments are not available. A mouse model of AAA formation involves chronic infusion of angiotensin II (AngII), and previous studies indicated a primary role for the AngII type 1a receptor in AAA formation. β-arrestin (βarr)-2 is a multifunctional scaffolding protein that binds G-protein–coupled receptors such as AngII type 1a and regulates numerous signaling pathways and pathophysiological processes. However, a role for βarr2 in AngII-induced AAA formation is currently unknown. Objective: To determine whether βarr2 played a role in AngII-induced AAA formation in mice. Methods and Results: Treatment of βarr2 +/+ and βarr2 −/− mice on the hyperlipidemic apolipoprotein E–deficient (apoE −/− ) background or on normolipidemic C57BL/6 background with AngII for 28 days indicated that βarr2 deficiency significantly attenuated AAA formation. βarr2 deficiency attenuated AngII-induced expression of cyclooxygenase-2, monocyte chemoattractant protein-1, macrophage inflammatory protein 1α, and macrophage infiltration. AngII also increased the levels of phosphorylated extracellular signal-regulated kinase 1/2 in apoE −/− /βarr2 +/+ aortas, whereas βarr2 deficiency diminished this increase. Furthermore, inhibition of extracellular signal-regulated kinase 1/2 activation with CI1040 (100 mg/kg per day) reduced the level of AngII-induced cyclooxygenase-2 expression in apoE −/− /βarr2 +/+ mice to the level observed in apoE −/− /βarr2 −/− mice. AngII treatment also increased matrix metalloproteinase expression and disruption of the elastic layer in apoE −/− /βarr2 +/+ aortas, and βarr2 deficiency reduced these effects. Conclusions: βarr2 contributes to AngII-induced AAA formation in mice by phosphorylated extracellular signal-regulated kinase 1/2–mediated cyclooxygenase-2 induction and increased inflammation. These studies suggest that for the AngII type 1a receptor, G-protein–independent, βarr2-dependent signaling plays a major role in AngII-induced AAA formation.