Article

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

1National Institute of Environmental Health Sciences, 111 T.W. Alexander Drive, MD C4-09, Durham, New York, 27709, UNITED STATES.
Circulation Research (Impact Factor: 11.09). 03/2013; DOI: 10.1161/CIRCRESAHA.112.280399
Source: PubMed

ABSTRACT 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.

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