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Granzyme B in abdominal aortic aneurysm and aortic dissection

University of British Columbia

An aneurysm is a permanent focal dilatation of an artery, often associated with atherosclerosis and with a weakening of the vessel wall. An arterial dissection is when a tear in the inner layer of the blood vessel causes blood to flow between the layers and force the blood vessel apart. Aneurysms or dissections can result in rupturing of the vessel, leading to excessive hemorrhaging and death if not immediately repaired. Granzyme B (GrB) is a protein that is expressed and secreted by cytotoxic immune cells. GrB has been identified as a key player in atherosclerosis both in the induction of apoptosis in target cells and the degradation of extracellular matrix proteins. We generated GrB/apolipoprotein E (apoE) double knockout (GrB/apoE-DKO) mice, and have shown that advanced atherosclerosis is significantly reduced in GrB/apoE-DKO mice as compared to apoE-KO mice. Evaluation of elastin staining indicated a loss of elastic tissue and medial thinning in the aortas of apoE-KO mice that was restored when GrB was absent in the GrB/apoE-DKO mice. Since medial thinning renders the aorta wall more susceptible to aneurysms or dissections, we hypothesize that the absence of GrB will reduce the incidence of aneurysm formation and dissection in GrB/apoE-DKO mice as compared to apoE-KO mice during angiotensin II (angli) infusion. To induce aortic dissections, 3-month-old C57 (wildtype), apoE-KO, and GrB/apoE-DKO mice were implanted with an osmotic mini pump which released a dose of 1000ng/kg/min of angli (or saline as a control) for 28 days. The mice were euthanized at 28 days, and the aortas were removed and evaluated for gross morphology and, after cross sectional staining, for histopathological lesions. A significant reduction in aortic dissections and aneurysms was observed in GrB/apoE-DKO mice as compared to apoE-KO mice treated with angII. Further, GrB deficiency corresponds to a significant increase in survival at the 28 day time-point. Aneurysms and dissections were not observed in the saline-treated groups or the angli-treated wild-type controls. In conclusion, our studies suggest that GrB contributes to the loss of vessel wall integrity and to the occurrence of aortic aneurysm and dissection.

Thesis/Dissertation

application/pdf

2009-03-05

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/5584

Pathology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/