Abstract 1428: Cyclophilin a Promotes Vascular Oxidative Stress and Accelerates Development of Angiotensin II-Induced Aortic Aneurysms

Abstract

Cyclophilin A (CyPA) is a chaperone protein secreted from vascular smooth muscle cells (VSMC) in response to reactive oxygen species (ROS), that stimulates VSMC migration and inflammatory cell migration in vitro. Abdominal aortic aneurysm (AAA) formation involves inflammatory cytokine release, leukocyte recruitment, aortic wall degradation, and neovascularization. We hypothesized that VSMC-derived CyPA contributes to AAA pathogenesis due to its proinflammatory properties. To determine the role of CyPA in AAA formation, ApoE −/− and ApoE −/− CyPA −/− mice were infused with angiotensin II (AngII, 1000 ng/min/kg) for 4 weeks. There were no differences in blood pressure and cholesterol between ApoE −/− and ApoE −/− CyPA −/− mice before and after Ang II treatment. AngII-induced AAA formation and aortic rupture was frequently observed in ApoE −/− mice (89% and 40%). In contrast, ApoE −/− CyPA −/− mice were completely protected from AngII-induced AAA formation and aortic rupture (0% and 0%). ApoE −/− CyPA −/− mice showed decreased levels of monocyte chemoattractant protein (MCP)-1 in the aorta and lacked elastic lamina degradation, microvessel formation, and aortic expansion. In response to AngII, recruitment of leukocytes to the aortic wall was markedly impaired in ApoE −/− CyPA −/− mice compared with ApoE −/− mice (counts/area; 8.6±4.3 vs. 60.0±13.8, P <0.01). The incidence of AAA was 63% in CyPA +/+ marrow-transplanted ApoE −/− mice, while the incidence of AAA in ApoE −/− CyPA −/− mice remained 0% after transplantation of CyPA +/+ bone marrow cells. In situ and gelatin zymography demonstrated that CyPA was required for matrix metalloproteinase (MMP) activation in aortic wall. Treatment of mouse aortic wild-type VSMC with AngII augmented MMP activity, which was significantly less in CyPA −/− VSMC. Treatment of VSMC with 100 nM CyPA augmented MMP activity, suggesting the importance of extracellular CyPA as well as intracellular CyPA. Finally, VSMC-specific CyPA overexpressing mice revealed augmented AngII-induced MMP activity in the vascular wall. Vascular-derived CyPA contributes to AAA pathogenesis in mice by increasing proinflammatory cytokine expression, inflammatory cell migration, and MMP activation. This research has received full or partial funding support from the American Heart Association, AHA Founders Affiliate (Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont).