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 angiotensin II type 1a (AT1a) receptor, in AAA formation. β-arrestin-2 (βarr2) is a multifunctional scaffolding protein that binds G-protein coupled receptors such as AT1a, and regulates numerous signaling pathways and pathophysiological processes. However, a role for βarr2 in AngII-induced AAA formation is currently unknown.
Objective: To determine if βarr2 played a role in AngII-induced AAA formation in mice.
Methods and Results: Treatment of βarr2+/+ and βarr2-/- mice on the hyperlipidemic ApoE-/-background or 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 (COX-2), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein 1α (MIP1α), and macrophage infiltration. AngII also increased the levels of phosphorylated-extracellular signal-regulated kinase 1/2 (p-ERK1/2) in ApoE-/-/ βarr2+/+ aortas, whereas βarr2 deficiency diminished this increase. Furthermore, inhibition of ERK1/2 activation with CI1040 (100mg/kg/day) reduced the level of AngII-induced COX-2 expression in ApoE-/-/ βarr2+/+ mice to the level observed in ApoE-/-/ βarr2-/- mice. AngII treatment also increased matrix metalloproteinase (MMP) 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 p-ERK1/2-mediated COX-2 induction and increased inflammation. These studies suggest that for the AT1a receptor, G-protein-independent, βarr2-dependent signaling plays a major role in AngII-induced AAA formation.
- Received August 22, 2012.
- Revision received March 20, 2013.
- Accepted March 22, 2013.