Abstract 518: Cyclophilin A is a Novel Pro-Inflammatory Cytokine that Accelerates Development of Atherosclerosis

Abstract

Background - Cyclophilin A (CyPA), a member of the immunophilin family, is highly expressed in vascular smooth muscle cells (VSMC) in mice and humans. CyPA is secreted in response to reactive oxygen species (ROS) and also is a positive regulator of helper T (Th) profile promoting differentiation of Th0 cells into Th1 lymphocytes (increased IFN-γ The development of atherosclerosis involves vascular inflammatory cytokine release, inflammatory cell migration/activation, and altered Th1/Th2 profile. Based on the role of CyPA in ROS signaling and Th profile we hypothesized that CyPA would promote atherosclerosis. Methods and Results - We compared atherosclerosis development in ApoE −/− and ApoE −/− CyPA −/− mice using two different models. In ApoE −/− mice fed a high-fat diet for 16 weeks, atherosclerosis assessed by oil-red O (ORO) staining was significantly greater in ApoE −/− mice compared to ApoE −/− CyPA −/− mice (%ORO, en face aorta; 23.1±5.5 vs. 6.8±3.2, P <0.01). Immunostaining of atherosclerotic lesions in the aortic cusp revealed the co-localization of CyPA, CD45, and MCP-1, suggesting the importance of CyPA for inflammatory cell recruitment and cytokine production. Angiotensin II infusion (AngII, 1000 ng/min/kg, 4 weeks) significantly increased atherosclerosis area in ApoE −/− mice, which was significantly less in ApoE −/− CyPA −/− mice (%ORO, en face aorta; 11.1±4.6 vs. 4.0±2.8, P<0.01). ApoE −/− mice showed significant increases in vascular MCP-1 expression, VCAM-1 expression, and inflammatory cell migration to the aortic wall, all of which were significantly less in ApoE −/− CyPA −/− mice. Cytokine/chemokine array analysis revealed that AngII significantly increased secretion of numerous cytokine/chemokines from ApoE −/− spleno-cytes, which was significantly less in ApoE −/− CyPA −/− splenocytes. Mechanistic studies in vitro revealed that AngII enhanced CyPA secretion from mouse aortic VSMC. Finally, expression of CyPA was significantly increased in atherosclerotic plaques of patients with acute coronary syndromes. Conclusion - CyPA is a novel mediator of atherosclerosis by promoting inflammatory cytokine/chemokine secretion, adhesion molecule expression, and inflammatory cell migration. 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).