Perforin-independent extracellular granzyme B activity contributes to abdominal aortic aneurysm.

TitlePerforin-independent extracellular granzyme B activity contributes to abdominal aortic aneurysm.
Publication TypeJournal Article
Year of Publication2010
AuthorsChamberlain, CM, Ang, LS, Boivin, WA, Cooper, DM, Williams, SJ, Zhao, H, Hendel, A, Folkesson, M, Swedenborg, J, Allard, MF, McManus, BM, Granville, DJ
JournalAm J Pathol
Date Published2010 Feb
KeywordsAngiotensin II, Animals, Aorta, Abdominal, Aortic Aneurysm, Abdominal, Apolipoproteins E, Extracellular Space, Granzymes, Humans, Immune System, Mice, Mice, Inbred C57BL, Mice, Knockout, Microfilament Proteins, Perforin, Protein Processing, Post-Translational, Tissue Distribution

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.

Alternate JournalAm. J. Pathol.
PubMed ID20035050
PubMed Central IDPMC2808106