title: Granzyme B Deficiency Protects against Angiotensin II-Induced Cardiac Fibrosis.
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.
authors.affiliation: 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.
authors.forename: Yue
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Biosciences, Turku Centre for Biotechnology, Åbo Akademi University, Turku, Finland.
authors.forename: Fang
authors.initials: F
authors.lastname: Cheng
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Mehul
authors.initials: M
authors.lastname: Sharma
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Merkulova
authors.affiliation: 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.
authors.forename: Sheetal A
authors.initials: SA
authors.lastname: Raithatha
authors.affiliation: 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.
authors.forename: Leigh G
authors.initials: LG
authors.lastname: Parkinson
authors.affiliation: 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.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Zhao
authors.affiliation: 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.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Westendorf
authors.affiliation: 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.
authors.forename: Lubos
authors.initials: L
authors.lastname: Bohunek
authors.affiliation: 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.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Bozin
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Ivy
authors.initials: I
authors.lastname: Hsu
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Lisa S
authors.initials: LS
authors.lastname: Ang
authors.affiliation: 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.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Williams
authors.affiliation: Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: R Chris
authors.initials: RC
authors.lastname: Bleackley
authors.affiliation: Department of Biosciences, Turku Centre for Biotechnology, Åbo Akademi University, Turku, Finland.
authors.forename: John E
authors.initials: JE
authors.lastname: Eriksson
authors.affiliation: 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.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Seidman
authors.affiliation: 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.
authors.forename: Bruce M
authors.initials: BM
authors.lastname: McManus
authors.affiliation: 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.
authors.forename: David J
authors.initials: DJ
authors.lastname: Granville
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis / Q000201:enzymology / Q000473:pathology; D005455:Fluorescent Antibody Technique; D053804:Granzymes / Q000378:metabolism*; D006331:Heart Diseases / Q000201:enzymology* / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D060888:Real-Time Polymerase Chain Reaction; D055815:Young Adult
chemical_list: D053804:Granzymes