Granzyme B Deficiency Protects against Angiotensin II Induced Cardiac Fibrosis
| Autor: | Yue Shen, Tatjana Bozin, Lubos Bohunek, John E. Eriksson, Lisa S. Ang, Yulia Merkulova, Ivy Hsu, Fang Cheng, David J. Granville, Kathryn Westendorf, Bruce M. McManus, Sheetal A. Raithatha, Sarah J. Williams, Hongyan Zhao, Michael A. Seidman, Leigh G. Parkinson, Mehul Sharma, R. Chris Bleackley |
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| Rok vydání: | 2016 |
| Předmět: |
Adult
Male 0301 basic medicine Heart Diseases Cardiac fibrosis Fluorescent Antibody Technique Inflammation Biology Real-Time Polymerase Chain Reaction ta3111 Granzymes Pathology and Forensic Medicine GZMB Mice Young Adult 03 medical and health sciences Fibrosis medicine Animals Humans Aged Mice Knockout Middle Aged medicine.disease Immunohistochemistry Angiotensin II 3. Good health Mice Inbred C57BL Granzyme B Disease Models Animal 030104 developmental biology Granzyme Perforin Immunology biology.protein Female medicine.symptom |
| Zdroj: | American Journal of Pathology. 186(1):87-100 |
| ISSN: | 0002-9440 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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