Perforin-independent extracellular granzyme B activity contributes to abdominal aortic aneurysm.
Granzyme B (GZMB) is a serine protease that is abundantly expressed in advanced human atherosclerotic lesions and may contribute to plaque instability. Perforin is a pore-forming protein that facilitates GZMB internalization and the induction of apoptosis. Recently a perforin-independent, extracellular role for GZMB has been proposed. In the current study, the role of GZMB in abdominal aortic aneurysm (AAA) was assessed. Apolipoprotein E (APOE)(-/-) x GZMB(-/-) and APOE(-/-) x perforin(-/-) double knockout (GDKO, PDKO) mice were generated to test whether GZMB exerted a causative role in aneurysm formation. To induce aneurysm, mice were given angiotensin II (1000 ng/kg/min) for 28 days. GZMB was found to be abundant in both murine and human AAA specimens. GZMB deficiency was associated with a decrease in AAA and increased survival compared with APOE-KO and PDKO mice. Although AAA rupture was observed frequently in APOE-KO (46.7%; n = 15) and PDKO (43.3%; n = 16) mice, rupture was rarely observed in GDKO (7.1%; n = 14) mice. APOE-KO mice exhibited reduced fibrillin-1 staining compared with GDKO mice, whereas in vitro protease assays demonstrated that fibrillin-1 is a substrate of GZMB. As perforin deficiency did not affect the outcome, our results suggest that GZMB contributes to AAA pathogenesis via a perforin-independent mechanism involving extracellular matrix degradation and subsequent loss of vessel wall integrity.
Chamberlain
Ciara M
CM
James Hogg Research Laboratories, Providence Heart and Lung Institute, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada, V6Z 1Y6.
Ang
Lisa S
LS
Boivin
Wendy A
WA
Cooper
Dawn M
DM
Williams
Sarah J
SJ
Zhao
Hongyan
H
Hendel
Alon
A
Folkesson
Maggie
M
Swedenborg
Jesper
J
Allard
Michael F
MF
McManus
Bruce M
BM
Granville
David J
DJ
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001012:Aorta, Abdominal / Q000378:metabolism / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D001057:Apolipoproteins E / Q000235:genetics; D005110:Extracellular Space / Q000378:metabolism; D000071838:Fibrillin-1; D000071837:Fibrillins; D053804:Granzymes / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D007107:Immune System / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D054353:Perforin / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011499:Protein Processing, Post-Translational / Q000235:genetics; D014018:Tissue Distribution; D054392:Adipokines
D000804:Angiotensin II; D001057:Apolipoproteins E; D000071838:Fibrillin-1; D000071837:Fibrillins; D053804:Granzymes; D008840:Microfilament Proteins; D054353:Perforin; C000605722:FBN1 protein, human; D054392:Adipokines; C000605724:Fbn1 protein, mouse