Details

Autor(en) / Beteiligte

• Shen, Yue
• Cheng, Fang
• Sharma, Mehul
• Merkulova, Yulia
• Raithatha, Sheetal A
• Parkinson, Leigh G
• Zhao, Hongyan
• Westendorf, Kathryn
• Bohunek, Lubos
• Bozin, Tatjana
• Hsu, Ivy
• Ang, Lisa S
• Williams, Sarah J
• Bleackley, R. Chris
• Eriksson, John E
• Seidman, Michael A
• McManus, Bruce M
• Granville, David J

Titel

Granzyme B Deficiency Protects against Angiotensin II–Induced Cardiac Fibrosis

Ist Teil von

• The American journal of pathology, 2016, Vol.186 (1), p.87-100

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2016

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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.