Abstract 13067: Cyclophilin A is an Inflammatory Mediator That Promotes Atherosclerosis in Apolipoprotein E-Deficient Mice
Background: Cyclophilin A (CyPA, encoded by Ppia) is a ubiquitously expressed protein secreted in response to pro-inflammatory stimuli. CyPA stimulates VSMC migration and proliferation, endothelial cell adhesion molecule expression and inflammatory cell chemotaxis. Given these activities, we hypothesized that CyPA is pro-atherogenic.
Methods and Results: In the high cholesterol diet fed Apoe-/- mouse CyPA deficiency led to a reduction of atherosclerosis (% Oil Red O, en face aorta; 19.3±7.5 in Apoe-/- vs. 8.2±2.0 in Apoe-/-Ppia-/- mice, P<0.01). CyPA deficiency was associated with decreased LDL uptake, inflammatory cell accumulation, and apoptosis. Moreover, en face staining of aortic tissues showed that VCAM-1 expression was significantly reduced in mice lacking CyPA. Importantly, eNOS protein expression was significantly higher in the Apoe-/-Ppia-/- mice compared to Apoe-/- mice. To define the mechanisms responsible for decreased eNOS expression, the effect of altering CyPA levels in cultured Human Umbilical Vein Endothelial Cells (HUVEC) was studied. Steady laminar flow at physiologic shear stress (12 dyn/cm2, termed s-flow here) increased eNOS expression and this effect was significantly increased by CyPA siRNA. Also, CyPA knock down in HUVEC increased eNOS promoter activity and eNOS mRNA levels. To substantiate further the role of CyPA in the regulation of eNOS expression, we transfected HUVEC with wild-type CyPA (CyPA-WT). Overexpression of CyPA was accompanied by down-regulation of eNOS at protein and mRNA levels. Consistent with the expression data, overexpression of CyPA decreased eNOS promoter activity in HUVEC. Finally, expression of CyPA was augmented in ruptured atherosclerotic plaques of patients with acute coronary syndromes.
Conclusion: These data show that CyPA is a negative regulator of eNOS expression which may contribute to the increased LDL uptake and VCAM-1 expression observed in atherosclerosis. CyPA may be a target for cardiovascular therapies.
- © 2010 by American Heart Association, Inc.