title: Modulation of Kinin B2 Receptor Signaling Controls Aortic Dilatation and Rupture in the Angiotensin II-Infused Apolipoprotein E-Deficient Mouse.
abstract: Abdominal aortic aneurysm (AAA) is an important cause of mortality in older adults. Activity of the local kallikrein-kinin system may be important in cardiovascular disease. The effect of kinin B2 receptor (B2R) agonist and antagonist peptides on experimental AAA was investigated.
  
  
  
  AAA was induced in apolipoprotein E-deficient mice via infusion of angiotensin II (1.0 μg/kg per minute SC). B2R agonists or antagonists were given via injection (2 mg/kg IP) every other day. The B2R agonist (B9772) promoted aortic rupture in response to angiotensin II associated with an increase in neutrophil infiltration of the aorta in comparison to controls. Mice receiving a B2R/kinin B1 receptor antagonist (B9430) were relatively protected from aortic rupture. Neutrophil depletion abrogated the ability of the B2R agonist to promote aortic rupture. Progression of angiotensin II-induced aortic dilatation was inhibited in mice receiving a B2R antagonist (B9330). Secretion of metalloproteinase-2 and -9, osteoprotegerin, and osteopontin by human AAA explant was reduced in the presence of the B2R antagonist (B9330). B2R agonist and antagonist peptides enhanced and inhibited, respectively, angiotensin II-induced neutrophil activation and aortic smooth muscle cell inflammatory phenotype. The B2R antagonist (B9330; 5 μg) delivered directly to the aortic wall 1 week post-AAA induction with calcium phosphate in a rat model reduced aneurysm growth associated with downregulation of aortic metalloproteinase-9.
  
  
  
  B2R signaling promotes aortic rupture within a mouse model associated with the ability to stimulate inflammatory phenotypes of neutrophils and vascular smooth muscle cells. B2R antagonism could be a potential therapy for AAA.
authors.affiliation: From the Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine & Dentistry (C.S.M., T.D., R.J.J., E.B., J.G.), and Discipline of Biomedicine, College of Public Health, Medical and Veterinary Sciences (C.M.R.), James Cook University, Townsville, Queensland, Australia; Department of Biochemistry, University of Colorado Denver, Aurora (L.G.); School of Surgery, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia (P.E.N.); and Department of Vascular and Endovascular Surgery, The Townsville Hospital, Townsville, Queensland, Australia (J.G.).
authors.forename: Corey S
authors.initials: CS
authors.lastname: Moran
authors.affiliation: From the Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine & Dentistry (C.S.M., T.D., R.J.J., E.B., J.G.), and Discipline of Biomedicine, College of Public Health, Medical and Veterinary Sciences (C.M.R.), James Cook University, Townsville, Queensland, Australia; Department of Biochemistry, University of Colorado Denver, Aurora (L.G.); School of Surgery, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia (P.E.N.); and Department of Vascular and Endovascular Surgery, The Townsville Hospital, Townsville, Queensland, Australia (J.G.).
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Rush
authors.affiliation: From the Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine & Dentistry (C.S.M., T.D., R.J.J., E.B., J.G.), and Discipline of Biomedicine, College of Public Health, Medical and Veterinary Sciences (C.M.R.), James Cook University, Townsville, Queensland, Australia; Department of Biochemistry, University of Colorado Denver, Aurora (L.G.); School of Surgery, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia (P.E.N.); and Department of Vascular and Endovascular Surgery, The Townsville Hospital, Townsville, Queensland, Australia (J.G.).
authors.forename: Tammy
authors.initials: T
authors.lastname: Dougan
authors.affiliation: From the Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine & Dentistry (C.S.M., T.D., R.J.J., E.B., J.G.), and Discipline of Biomedicine, College of Public Health, Medical and Veterinary Sciences (C.M.R.), James Cook University, Townsville, Queensland, Australia; Department of Biochemistry, University of Colorado Denver, Aurora (L.G.); School of Surgery, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia (P.E.N.); and Department of Vascular and Endovascular Surgery, The Townsville Hospital, Townsville, Queensland, Australia (J.G.).
authors.forename: Roby J
authors.initials: RJ
authors.lastname: Jose
authors.affiliation: From the Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine & Dentistry (C.S.M., T.D., R.J.J., E.B., J.G.), and Discipline of Biomedicine, College of Public Health, Medical and Veterinary Sciences (C.M.R.), James Cook University, Townsville, Queensland, Australia; Department of Biochemistry, University of Colorado Denver, Aurora (L.G.); School of Surgery, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia (P.E.N.); and Department of Vascular and Endovascular Surgery, The Townsville Hospital, Townsville, Queensland, Australia (J.G.).
authors.forename: Erik
authors.initials: E
authors.lastname: Biros
authors.affiliation: From the Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine & Dentistry (C.S.M., T.D., R.J.J., E.B., J.G.), and Discipline of Biomedicine, College of Public Health, Medical and Veterinary Sciences (C.M.R.), James Cook University, Townsville, Queensland, Australia; Department of Biochemistry, University of Colorado Denver, Aurora (L.G.); School of Surgery, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia (P.E.N.); and Department of Vascular and Endovascular Surgery, The Townsville Hospital, Townsville, Queensland, Australia (J.G.).
authors.forename: Paul E
authors.initials: PE
authors.lastname: Norman
authors.affiliation: From the Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine & Dentistry (C.S.M., T.D., R.J.J., E.B., J.G.), and Discipline of Biomedicine, College of Public Health, Medical and Veterinary Sciences (C.M.R.), James Cook University, Townsville, Queensland, Australia; Department of Biochemistry, University of Colorado Denver, Aurora (L.G.); School of Surgery, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia (P.E.N.); and Department of Vascular and Endovascular Surgery, The Townsville Hospital, Townsville, Queensland, Australia (J.G.).
authors.forename: Lajos
authors.initials: L
authors.lastname: Gera
authors.affiliation: From the Vascular Biology Unit, Queensland Research Centre for Peripheral Vascular Disease, School of Medicine & Dentistry (C.S.M., T.D., R.J.J., E.B., J.G.), and Discipline of Biomedicine, College of Public Health, Medical and Veterinary Sciences (C.M.R.), James Cook University, Townsville, Queensland, Australia; Department of Biochemistry, University of Colorado Denver, Aurora (L.G.); School of Surgery, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia (P.E.N.); and Department of Vascular and Endovascular Surgery, The Townsville Hospital, Townsville, Queensland, Australia (J.G.). jonathan.golledge@jcu.edu.au.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Golledge
mesh_terms: D000804:Angiotensin II; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D001019:Aortic Rupture / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D065094:Bradykinin B2 Receptor Antagonists / Q000494:pharmacology; D002130:Calcium Phosphates; D004108:Dilatation, Pathologic; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D018345:Mice, Knockout; D018375:Neutrophil Activation / Q000187:drug effects; D053495:Osteopontin / Q000378:metabolism; D053244:Osteoprotegerin / Q000378:metabolism; D010641:Phenotype; D017207:Rats, Sprague-Dawley; D043782:Receptor, Bradykinin B2 / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D046509:Tissue Culture Techniques
chemical_list: D001057:Apolipoproteins E; C121351:B 9430; D065094:Bradykinin B2 Receptor Antagonists; D002130:Calcium Phosphates; D053244:Osteoprotegerin; D043782:Receptor, Bradykinin B2; C506895:SPP1 protein, human; C506030:TNFRSF11B protein, human; D053495:Osteopontin; D000804:Angiotensin II; C020243:calcium phosphate; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat; D001920:Bradykinin
keywords: abdominal aortic aneurysm; angiotensin II; animal model cardiovascular disease; aorta; bradykinin; kinins