UBC Theses and Dissertations

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UBC Theses and Dissertations

Granzyme K : a novel contributor in cardiac allograft vasculopathy Tauh, Keerit


Background - A major factor limiting survival for patients that have undergone cardiac transplantation is cardiac allograft vasculopathy (CAV). CAV is a fibroproliferative inflammatory form of vascular rejection mediated by immune cells and which is initiated upon damage to the graft endothelium and medial smooth muscle cells (SMC). Granzymes are a family of five serine proteases in humans. Granzymes have been shown to exert roles in cell death, endothelial dysfunction, inflammation and matrix remodeling. Granzyme K (GzmK) specifically can promote endothelial dysfunction and the production of inflammatory mediators IL-1β, IL-6, and monocyte chemotactic protein-1. As such, we hypothesized that GzmK contributes to CAV. Methods - An infrarenal aortic interposition graft was completed across a complete major histocompatibility complex (MHC)-mismatch with recipients being either wildtype or GzmK-KO mice. Allografts were then assessed for CAV severity and compared to human CAV samples. The effects of GzmK on human SMC were also assessed in vitro. Given that atherosclerosis shares similar underlying mechanisms to CAV, GzmK deposition was also characterized in atherosclerosis. Results - Human CAV samples demonstrated increased neointimal GzmK deposition as compared to unaffected native coronaries (p= 0.017). GzmK primarily localized to the medial and neointimal layers. Similar deposition patterns were observed in murine transplants. When the role of GzmK was examined, GzmK deficiency resulted in reduced CAV with less neointima formation (p=0.019) and less luminal obstruction (p

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