title: Perforin and granzyme B have separate and distinct roles during atherosclerotic plaque development in apolipoprotein E knockout mice.
abstract: The granzyme B/perforincytotoxic pathway is a well established mechanism of initiating target cell apoptosis. Previous studies have suggested a role for the granzyme B/perforin cytotoxic pathway in vulnerable atherosclerotic plaque formation. In the present study, granzyme B deficiency resulted in reduced atherosclerotic plaque development in the descending aortas of apolipoprotein E knockout mice fed a high fat diet for 30 weeks while perforindeficiency resulted in greater reduction in plaque development with significantly less plaque area than granzyme Bdeficient mice. In contrast to the descending aorta, no significant change in plaque size was observed in aortic roots from either granzyme Bdeficient or perforindeficient apolipoprotein E knockout mice. However, atherosclerotic plaques in the aortic roots did exhibit significantly more collagen in granzyme B, but not perforin deficient mice. Together these results suggest significant, yet separate roles for granzyme B and perforin in the pathogenesis of atherosclerosis that go beyond the traditional apoptotic pathway with additional implications in plaque development, stability and remodelling of extracellular matrix.
authors.affiliation: UBC James Hogg Research Centre at the Institute for Heart + Lung Health, St. Paul's Hospital, Vancouver, British Columbia, Canada ; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Hiebert
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Boivin
authors.forename: Hongyan
authors.initials: H
authors.lastname: Zhao
authors.forename: Bruce M
authors.initials: BM
authors.lastname: McManus
authors.forename: David J
authors.initials: DJ
authors.lastname: Granville
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics*; D003094:Collagen / Q000378:metabolism; D058575:Decorin / Q000378:metabolism; D059305:Diet, High-Fat; D055786:Gene Knockout Techniques; D053804:Granzymes / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D050356:Lipid Metabolism; D018345:Mice, Knockout; D054353:Perforin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D058226:Plaque, Atherosclerotic / Q000473:pathology*
chemical_list: D001057:Apolipoproteins E; C546879:Dcn protein, mouse; D058575:Decorin; D054353:Perforin; D003094:Collagen; D053804:Granzymes