Granzyme B deficiency protects against angiotensin II–induced cardiac fibrosis

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 Eriksson, Michael A. Seidman, Bruce M. McManus, David J. Granville

Tutkimustuotos: LehtiartikkeliArtikkeliTieteellinenvertaisarvioitu

22 Sitaatiot (Scopus)

Abstrakti

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.
AlkuperäiskieliEi tiedossa
Sivut87–100
Sivumäärä14
JulkaisuAmerican Journal of Pathology
Vuosikerta186
Numero1
DOI - pysyväislinkit
TilaJulkaistu - 2016
OKM-julkaisutyyppiA1 Julkaistu artikkeli, soviteltu

Viittausmuodot