Kallikrein-1 Blockade Inhibits Aortic Expansion in a Mouse Model and Reduces Prostaglandin E2 Secretion From Human Aortic Aneurysm Explants
| Autor: | Jonathan Golledge, Smriti M. Krishna, Susan K. Morton, Daniel J. Sexton, Corey S. Moran, Erik Biros |
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| Rok vydání: | 2021 |
| Předmět: |
Male
medicine.medical_specialty kallikrein‐1 Biopsy Bradykinin Vascular Medicine Dinoprostone Muscle Smooth Vascular Aortic aneurysm chemistry.chemical_compound Mice Internal medicine medicine.artery Blocking antibody Vascular Disease medicine Animals Humans cardiovascular diseases Aorta Abdominal Prostaglandin E2 Cells Cultured Original Research Metalloproteinase Kininogen Aorta prostaglandin E2 business.industry cyclooxygenase‐2 Kinin medicine.disease enzymes and coenzymes (carbohydrates) Disease Models Animal Endocrinology chemistry cardiovascular system Disease Progression aneurysm Cardiology and Cardiovascular Medicine business Tissue Kallikreins medicine.drug circulatory and respiratory physiology Aortic Aneurysm Abdominal |
| Zdroj: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| ISSN: | 2047-9980 |
| Popis: | BackgroundAbdominal 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 E2in human AAA explants.Methods and ResultsNeutralization 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 E2and 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 E2and active matrix metalloproteinase 2 and matrix metalloproteinase 9 from human AAA explants and vascular smooth muscle cells exposed to activated neutrophils.ConclusionsThese findings suggest that kallikrein‐1 neutralization could be a treatment target for AAA. |
| Databáze: | OpenAIRE |
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