Granzyme B induces smooth muscle cell apoptosis in the absence of perforin: involvement of extracellular matrix degradation.

Autor:	Choy JC; The James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada., Hung VH, Hunter AL, Cheung PK, Motyka B, Goping IS, Sawchuk T, Bleackley RC, Podor TJ, McManus BM, Granville DJ
Jazyk:	angličtina
Zdroj:	Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2004 Dec; Vol. 24 (12), pp. 2245-50. Date of Electronic Publication: 2004 Oct 07.
DOI:	10.1161/01.ATV.0000147162.51930.b7
Abstrakt:	Objective: T cell-induced cytotoxicity, of which granzyme B is a key mediator, is believed to contribute to the pathogenesis of inflammatory vascular diseases. In this report, we investigate the mechanism of granzyme B-induced smooth muscle cell (SMC) death. Methods and Results: The addition of purified granzyme B alone to cultured SMCs caused a significant reduction in cell viability. Chromatin condensation, phosphatidylserine externalization, and membrane blebbing were observed, indicating that the mechanism of granzyme B-induced SMC death was through apoptosis. Activated splenocytes from perforin-knockout mice induced SMC death through a granzyme B-mediated pathway. Inhibition of the proteolytic activities of caspases and granzyme B prevented granzyme B-induced SMC death, whereas attenuation of granzyme B internalization with mannose-6-phosphate (M6P) did not. Further, granzyme B induced the cleavage of several SMC extracellular proteins, including fibronectin, and reduced focal adhesion kinase phosphorylation. Conclusions: These results indicate that granzyme B can induce apoptosis of SMCs in the absence of perforin by cleaving extracellular proteins, such as fibronectin.
Databáze:	MEDLINE
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