Granzyme B deficiency protects against angiotensin II–induced cardiac fibrosis

A1 Journal article (refereed)


Internal Authors/Editors


Publication Details

List of 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
Publisher: ELSEVIER SCIENCE INC
Publication year: 2016
Journal: American Journal of Pathology
Journal acronym: AM J PATHOL
Volume number: 186
Issue number: 1
Start page: 87
End page: 100
Number of pages: 14
ISSN: 0002-9440
eISSN: 1525-2191


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)-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.

Last updated on 2019-10-12 at 04:28