Modulation of Kinin B2 receptor signaling controls aortic dilatation and rupture in the Angiotensin II-infused apolipoprotein E-deficient mouse

C.S. Moran, C.M. Rush, T. Dougan, R.J. Jose, E. Biros, Paul Norman, L. Gera, J. Golledge

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    © 2016 American Heart Association, Inc. Objective - 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. Approach and Results - 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. Conclusions - 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.
    Original languageEnglish
    Pages (from-to)898-907
    Number of pages10
    JournalArteriosclerosis, thrombosis, and vascular biology
    Issue number5
    Early online date10 Mar 2016
    Publication statusPublished - May 2016


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