title: β-Arrestin-2 deficiency attenuates abdominal aortic aneurysm formation in mice.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Laboratory of Toxicology and Pharmacology, Comparative Medicine Branch, and Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Darshini B
authors.initials: DB
authors.lastname: Trivedi
authors.forename: Charles D
authors.initials: CD
authors.lastname: Loftin
authors.forename: James
authors.initials: J
authors.lastname: Clark
authors.forename: Page
authors.initials: P
authors.lastname: Myers
authors.forename: Laura M
authors.initials: LM
authors.lastname: DeGraff
authors.forename: Jennifer
authors.initials: J
authors.lastname: Cheng
authors.forename: Darryl C
authors.initials: DC
authors.lastname: Zeldin
authors.forename: Robert
authors.initials: R
authors.lastname: Langenbach
mesh_terms: D000804:Angiotensin II; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D019390:Arrestins / Q000172:deficiency* / Q000235:genetics; D001549:Benzamides / Q000494:pharmacology; D001794:Blood Pressure; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism; D054405:Chemokine CCL3 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D004547:Elastic Tissue / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D013997:Time Factors; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C120227:2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide; D001057:Apolipoproteins E; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D001549:Benzamides; C491768:Ccl2 protein, mouse; C496534:Ccl3 protein, mouse; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D047428:Protein Kinase Inhibitors; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D000804:Angiotensin II; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse