Extracellular Granzyme B: a key player in aneurysm pathogenesis (P3072)

Abstract

Abstract Granzyme B (GZMB) is a pro-apoptotic protease that is released by cytotoxic immune cells and internalized by target cells in a perforin-dependent manner. However, GZMB contributes to aortic aneurysm pathogenesis through a perforin-independent, extracellular process involving extracellular matrix proteolysis. In vitro and in vivo studies have identified decorin, a key regulator of collagen organization, fibrillogenesis and collagen tensile strength, as a GZMB substrate. We hypothesized that GZMB contributes to aortic aneurysm through the degradation of decorin leading to reduced collagen organization and tensile strength resulting in aortic rupture. To induce aneurysm, apoE-/- mice were implanted with osmotic minipumps that constitutively released angiotensin II. Mice were injected with the GZMB inhibitors, serpin A3N or anti-GZMB neutralizing antibody. A dose-dependent reduction in the frequency of aneurysm rupture was observed in mice that received inhibitor. Reduced GZMB and decorin proteolysis were observed in inhibitor-treated mice. Adventitial collagen from serpin-treated mice exhibited higher fibre density and reduced fibril size irregularity. GZMB was also elevated in human aortic aneurysm. GzmB was expressed in lymphocytes in the intraluminal thrombus and in mast cells in the aneurismal aortic adventitia. In summary, extracellular GZMB contributes to decorin degradation resulting in reduced collagen organization and loss of aortic wall integrity leading to aneurysm.