Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 186, Issue 1, Pages 87-100Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2015.09.010
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Funding
- Canadian Institutes of Health Research (CIHR) [MOP 332654, MOP 133518]
- CIHR
- Academy of Finland grant
- Frederick Banting and Charles Best Canada Graduate Scholarships
- MITACS Accelerate Postdoctoral Fellowship
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Cardiac fibrosis is observed across diverse etiologies of heart failure. Granzyme B (GzmB) is a serine protease involved in cell-mediated cytotoxicity in conjunction with the pore-forming protein, perforin. Recent evidence suggests that GzmB also contributes to matrix remodeling and fibrosis through an extracellular, perforin-independent process. However, the role of GzmB in the onset and progression of cardiac fibrosis remains elusive. The present study investigated the role of GzmB in the pathogenesis of cardiac fibrosis. GzmB was elevated in fibrotic human hearts and in angiotensin II-induced murine cardiac fibrosis. Genetic deficiency of GzmB reduced angiotensin II-induced cardiac hypertrophy and fibrosis, independently of perforin. GzmB deficiency also reduced microhemorrhage, inflammation, and fibroblast accumulation in vivo. In vitro, GzmB cleaved the endothelial junction protein, vascular endothelial (VE)-cadhetin, resulting in the disruption of endothelial barrier function. Together, these results suggest a perforin-independent, extracellular rote for GzmB in the pathogenesis of cardiac fibrosis.
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