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	Yue Shen, Fang Cheng, Mehul Sharma, Yulia Merkulova, Sheetal A Raithatha, Leigh G Parkinson, Hongyan Zhao, Kathryn Westendorf, Lubos Bohunek, Tatjana Bozin, Ivy Hsu, Lisa S Ang, Sarah J Williams, R Chris Bleackley, John E Eriksson, Michael A Seidman, Bruce M McManus, David J Granville
Journal	The American journal of pathology (Am J Pathol) Vol. 186 Issue 1 Pg. 87-100 (Jan 2016) ISSN: 1525-2191 [Electronic] United States
PMID	26610869 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright	Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Chemical References	Granzymes
Topics	Adult Aged Animals Disease Models, Animal Female Fibrosis (enzymology, pathology) Fluorescent Antibody Technique Granzymes (metabolism) Heart Diseases (enzymology, pathology) Humans Immunohistochemistry Male Mice Mice, Inbred C57BL Mice, Knockout Middle Aged Real-Time Polymerase Chain Reaction Young Adult

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