Abstract 11078: Granzyme B Deficiency Protects Against Angiotensin II-induced Cardiac Fibrosis via a Perforin-independent Mechanism
Introduction: Granzyme B (GzmB) is a serine protease involved in immune cell-mediated apoptosis that is enabled through a mechanism involving the pore-forming protein, perforin that facilitates internalization. However, recent evidence suggests that GzmB contributes to matrix remodeling and fibrosis through an extracellular, perforin-independent process.
Hypothesis: GzmB contributes to cardiac fibrosis through a perforin-independent pathway involving extracellular proteolysis.
Methods: Using a murine model of Angiotensin II (Ang II)-induced cardiac fibrosis, wild-type, GzmB deficient and Perforin deficient mice were treated with Ang II for 4 weeks, and were examined for the presence of cardiac fibrosis. Echocardiography was performed in these mice to examine the cardiac function. The level of Inflammation and inflammatory cells infiltration were examined by immunohistochemistry and RT-PCR analysis. The in vitro endothelial barrier function was measured by electric cell-substrate impedance sensing.
Results: GzmB was highly up-regulated in both murine and human cardiac fibrosis. Genetic deficiency of GzmB markedly reduced Ang II-induced cardiac dysfunction, hypertrophy and fibrosis, independently of perforin. GzmB deficiency also decreases microhemorrhage, inflammation, and fibroblast accumulation in vivo. In vitro studies identified VE-cadherin as a GzmB substrate. VE-cadherin is a key endothelial cell-cell junction protein. GzmB-mediated VE-cadherin cleavage resulted in increased endothelial permeability, and increased transcellular conductance. These results were also observed in vivo.
Conclusions: GzmB contributes to the onset and progression of cardiac fibrosis through a perforin-independent process involving the cleavage of VE-cadherin.
Author Disclosures: Y. Shen: None. F. Cheng: None. M. Sharma: None. Y. Merkulova: None. S.A. Raithatha: None. L.G. Parkinson: None. H. Zhao: None. K. Westendorf: None. L. Bohunek: None. T. Bozin: None. I. Hsu: None. L.S. Ang: None. S.J. Williams: None. R.C. Bleackley: None. J.E. Eriksson: None. M.A. Seidman: None. B.M. McManus: None. D.J. Granville: Ownership Interest; Significant; Dr. Granville is the Founder of viDA Therpeutics Inc.. Consultant/Advisory Board; Significant; Dr. Granville is the Chief Scientific Officer of viDA Therpeutics Inc..
- © 2015 by American Heart Association, Inc.