Modulation of kinin B2 receptor signaling controls aortic dilatation and rupture in the angiotensin II-infused apolipoprotein e-deficient mouse.

Moran, Corey S., Rush, Catherine M., Dougan, Tammy, Jose, Roby J., Biros, Erik, Norman, Paul E., Gera, Lajos, and Golledge, Jonathan (2016) Modulation of kinin B2 receptor signaling controls aortic dilatation and rupture in the angiotensin II-infused apolipoprotein e-deficient mouse. Arteriosclerosis, Thrombosis and Vascular Biology, 36 (5). pp. 898-907.

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Abstract

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 [mu]g/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 [mu]g) 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.

Item ID: 44733
Item Type: Article (Research - C1)
ISSN: 1524-4636
Keywords: abdominal aortic aneurysm, angiotensin II, animal model cardiovascular disease, aorta, bradykinin, kinins
Funders: National Health and Medical Research Council (NHMRC), Queensland Government
Projects and Grants: NHMRC Grant No. 1079369, 1079193, 1021416, 540403, 1000967, and 1098717, NHMRC Practitioner Fellowship 1019921
Date Deposited: 01 Aug 2016 23:56
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1102 Cardiovascular Medicine and Haematology > 110201 Cardiology (incl Cardiovascular Diseases) @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920103 Cardiovascular System and Diseases @ 100%
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