Bilirubin Prevents Atherosclerotic Plaque Formation In Ldlr-/- Mice By Inhibiting Monocyte Migration Through The Disruption Of Endothelial Vascular Cell Adhesion Molecule 1 (Vcam-1) And Intercellular Adhesion Molecule 1 (Icam-1) Signaling

Background: Epidemiologic studies support an inverse association between serum bilirubin levels and the risk of cardiovascular disease. Monocyte infiltration into the vascular endothelium, a critical early step in atherosclerotic plaque formation, is mediated primarily by the adhesion molecules VCAM-1 and ICAM-1. We postulate that bilirubin, a potent antioxidant, inhibits plaque formation by preventing monocyte transendothelial migration through the scavenging of VCAM-1 and ICAM-1 reactive oxygen species (ROS) signaling intermediaries. Methods: The effect of physiological concentrations (≤ 1.2 mg/dL) of bilirubin on the migration of THP-1 monocytes across HUVEC monolayers activated with TNFα to express VCAM-1 and ICAM-1 was assessed by Boyden chamber assay. The influence of bilirubin on monocyte adhesion, cytokine production, and VCAM-1- and ICAM-1-mediated ROS production was quantified by fluorescence assay, RT-PCR, and time-lapse confocal microscopy, respectively. To evaluate the effect on plaque format...