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Am J Pathol. 2016 Jan;186(1):87-100. doi: 10.1016/j.ajpath.2015.09.010. Epub 2015 Nov 25.

Granzyme B Deficiency Protects against Angiotensin II-Induced Cardiac Fibrosis.

Author information

1
Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
2
Department of Biosciences, Turku Centre for Biotechnology, Åbo Akademi University, Turku, Finland.
3
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
4
Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.
5
Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, Providence Health Care, Vancouver, British Columbia, Canada.
6
Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: david.granville@hli.ubc.ca.

Abstract

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)-cadherin, resulting in the disruption of endothelial barrier function. Together, these results suggest a perforin-independent, extracellular role for GzmB in the pathogenesis of cardiac fibrosis.

PMID:
26610869
DOI:
10.1016/j.ajpath.2015.09.010
[Indexed for MEDLINE]

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