Abstract 5463: Cyclophilin A Mediates Endothelial Damage and Promotes Recruitment of Inflammatory Cells and Atherosclerosis

Abstract

Background- Cyclophilin A (CyPA) is a proinflammatory cytokine that is highly expressed in vascular smooth muscle cells (VSMC) in mice and humans and is also secreted from VSMC in response to reactive oxygen species (ROS). Development of atherosclerosis involves endothelial cell (EC) dysfunction and activation, vascular inflammatory cytokine release, macrophage migration/activation, and differentiation into foam cells. Based on involvement of CyPA in ROS signaling, we hypothesized that CyPA expression would be proatherogenic. Methods and Results- Using the ApoE −/− mouse model, we compared atherosclerosis development following genetic deletion of CyPA (ApoE −/− CyPA −/− ) in mice fed a high fat diet for 16 wks. Atherosclerosis was assessed by oil-red O (ORO) staining and was significantly greater in ApoE −/− mice compared with ApoE −/− CyPA −/− mice (% ORO, en face aorta; 19.3±7.5 vs. 8.2±2.0, P <0.01). Immunostaining of aortic cusp revealed significant reduction of CD45 + cells, CD3 + cells, and Mac3 + cells in ApoE −/− CyPA −/− compared with ApoE −/− mice, supporting the role of CyPA in inflammatory cell recruitment. En face aortic TUNEL staining revealed significant reduction of EC apoptosis in ApoE −/− CyPA −/− compared with ApoE −/− mice (count/area; 23.1±5.5 vs. 6.8±3.2, P <0.01). Moreover, ApoE −/− CyPA −/− mice had reduced expression of vascular cellular adhesion molecule 1 (VCAM-1) and increased expression of eNOS compared to ApoE −/− mice, suggesting a key role for CyPA in EC inflammation. These features were not altered by reconstitution of bone marrow cells from ApoE −/− CyPA −/− mice, suggesting that vascular-derived CyPA plays a crucial role in progression of atherosclerosis. Mechanistic experiments revealed that CyPA may be important for MCP-1 secretion from VSMC. These data are consistent with findings in humans where expression of CyPA, migration of inflammatory cells, and adhesion molecule expression are significantly augmented in ruptured atherosclerotic plaque areas of patients with acute coronary syndromes. Conclusion- CyPA is a novel mediator of atherogenesis by promoting EC damage, adhesion molecule expression, and inflammatory cell migration.