| First Author | Trivedi DB | Year | 2013 |
| Journal | Circ Res | Volume | 112 |
| Issue | 9 | Pages | 1219-29 |
| PubMed ID | 23524589 | Mgi Jnum | J:213307 |
| Mgi Id | MGI:5584071 | Doi | 10.1161/CIRCRESAHA.112.280399 |
| Citation | Trivedi DB, et al. (2013) beta-Arrestin-2 deficiency attenuates abdominal aortic aneurysm formation in mice. Circ Res 112(9):1219-29 |
| abstractText | 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. beta-arrestin (betaarr)-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 betaarr2 in AngII-induced AAA formation is currently unknown. OBJECTIVE: To determine whether betaarr2 played a role in AngII-induced AAA formation in mice. METHODS AND RESULTS: Treatment of betaarr2(+/+) and betaarr2(-/-) mice on the hyperlipidemic apolipoprotein E-deficient (apoE(-/-)) background or on normolipidemic C57BL/6 background with AngII for 28 days indicated that betaarr2 deficiency significantly attenuated AAA formation. betaarr2 deficiency attenuated AngII-induced expression of cyclooxygenase-2, monocyte chemoattractant protein-1, macrophage inflammatory protein 1alpha, and macrophage infiltration. AngII also increased the levels of phosphorylated extracellular signal-regulated kinase 1/2 in apoE(-/-)/betaarr2(+/+) aortas, whereas betaarr2 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(-/-)/betaarr2(+/+) mice to the level observed in apoE(-/-)/betaarr2(-/-) mice. AngII treatment also increased matrix metalloproteinase expression and disruption of the elastic layer in apoE(-/-)/betaarr2(+/+) aortas, and betaarr2 deficiency reduced these effects. CONCLUSIONS: betaarr2 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, betaarr2-dependent signaling plays a major role in AngII-induced AAA formation. |
