Granzyme B deficiency protects against angiotensin II–induced cardiac fibrosis

A1 Originalartikel i en vetenskaplig tidskrift (referentgranskad)


Interna författare/redaktörer


Publikationens författare: 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
Förläggare: ELSEVIER SCIENCE INC
Publiceringsår: 2016
Tidskrift: American Journal of Pathology
Tidskriftsakronym: AM J PATHOL
Volym: 186
Nummer: 1
Artikelns första sida, sidnummer: 87
Artikelns sista sida, sidnummer: 100
Antal sidor: 14
ISSN: 0002-9440
eISSN: 1525-2191


Abstrakt

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.

Senast uppdaterad 2019-13-11 vid 03:17