Kallikrein-1 blockade inhibits aortic expansion in a mouse model and reduces prostaglandin E2 secretion from human aortic aneurysm explants

Moran, Corey S., Biros, Erik, Krishna, Smriti M., Morton, Susan K., Sexton, Daniel, and Golledge, Jonathan (2021) Kallikrein-1 blockade inhibits aortic expansion in a mouse model and reduces prostaglandin E2 secretion from human aortic aneurysm explants. Journal of the American Heart Association, 10 (5).

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Abstract

Background: Abdominal aortic aneurysm (AAA) is an important cause of mortality in older adults. The kinin B2 receptor agonist, bradykinin, has been implicated in AAA pathogenesis through promoting inflammation. Bradykinin is generated from high- and low-molecular-weight kininogen by the serine protease kallikrein-1. The aims of this study were first to examine the effect of neutralizing kallikrein-1 on AAA development in a mouse model and second to test how blocking kallikrein-1 affected cyclooxygenase-2 and prostaglandin E2 in human AAA explants.

Methods and Results: Neutralization of kallikrein-1 in apolipoprotein E-deficient (ApoE-/-) mice via administration of a blocking antibody inhibited suprarenal aorta expansion in response to angiotensin (Ang) II infusion. Kallikrein-1 neutralization decreased suprarenal aorta concentrations of bradykinin and prostaglandin E2 and reduced cyclooxygenase-2 activity. Kallikrein-1 neutralization also decreased protein kinase B and extracellular signal-regulated kinase 1/2 phosphorylation and reduced levels of active matrix metalloproteinase 2 and matrix metalloproteinase 9. Kallikrein-1 blocking antibody reduced levels of cyclooxygenase-2 and secretion of prostaglandin E2 and active matrix metalloproteinase 2 and matrix metalloproteinase 9 from human AAA explants and vascular smooth muscle cells exposed to activated neutrophils.

Conclusions: These findings suggest that kallikrein-1 neutralization could be a treatment target for AAA.

Item ID: 67075
Item Type: Article (Research - C1)
ISSN: 2047-9980
Keywords: aneurysm; cyclooxygenase‐2; kallikrein‐1; prostaglandin E2
Copyright Information: © 2021 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative Commons Attribution- NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
Funders: National Health and Medical Research Council of Australia (NHMRC)
Projects and Grants: NHMRC 1098717, NHMRC 1079369
Date Deposited: 17 Jun 2021 01:46
FoR Codes: 32 BIOMEDICAL AND CLINICAL SCIENCES > 3201 Cardiovascular medicine and haematology > 320199 Cardiovascular medicine and haematology not elsewhere classified @ 100%
SEO Codes: 20 HEALTH > 2001 Clinical health > 200105 Treatment of human diseases and conditions @ 100%
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