title: Bilirubin Prevents Atherosclerotic Lesion Formation in Low-Density Lipoprotein Receptor-Deficient Mice by Inhibiting Endothelial VCAM-1 and ICAM-1 Signaling.
abstract: BACKGROUND
  Numerous epidemiological studies support an inverse association between serum bilirubin levels and the incidence of cardiovascular disease; however, the mechanism(s) by which bilirubin may protect against atherosclerosis is undefined. The goals of the present investigations were to assess the ability of bilirubin to prevent atherosclerotic plaque formation in low-density lipoprotein receptor-deficient (Ldlr-/-) mice and elucidate the molecular processes underlying this effect.
  
  
  RESULTS
  Bilirubin, at physiological concentrations (≤20 μmol/L), dose-dependently inhibits THP-1 monocyte migration across tumor necrosis factor α-activated human umbilical vein endothelial cell monolayers without altering leukocyte binding or cytokine production. A potent antioxidant, bilirubin effectively blocks the generation of cellular reactive oxygen species induced by the cross-linking of endothelial vascular cell adhesion molecule 1 (VCAM-1) or intercellular adhesion molecule 1 (ICAM-1). These findings were validated by treating cells with blocking antibodies or with specific inhibitors of VCAM-1 and ICAM-1 signaling. When administered toLdlr-/-mice on a Western diet, bilirubin (30 mg/kg intraperitoneally) prevents atherosclerotic plaque formation, but does not alter circulating cholesterol or chemokine levels. Aortic roots from bilirubin-treated animals exhibit reduced lipid and collagen deposition, decreased infiltration of monocytes and lymphocytes, fewer smooth muscle cells, and diminished levels of chlorotyrosine and nitrotyrosine, without changes in VCAM-1 or ICAM-1 expression.
  
  
  CONCLUSIONS
  Bilirubin suppresses atherosclerotic plaque formation inLdlr-/-mice by disrupting endothelial VCAM-1- and ICAM-1-mediated leukocyte migration through the scavenging of reactive oxygen species signaling intermediaries. These findings suggest a potential mechanism for the apparent cardioprotective effects of bilirubin.
authors.affiliation: Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH vogelmn@mail.uc.edu megan.e.vogel@vanderbilt.edu.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Vogel
authors.affiliation: Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH.
authors.forename: Gila
authors.initials: G
authors.lastname: Idelman
authors.affiliation: Department of Pathology and Laboratory Medicine, Metabolic Disease Institute, University of Cincinnati College of Medicine, Cincinnati, OH.
authors.forename: Eddy S
authors.initials: ES
authors.lastname: Konaniah
authors.affiliation: Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Zucker
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001663:Bilirubin / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects*; D003094:Collagen / Q000378:metabolism; D066273:Diet, Western; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects* / Q000378:metabolism; D050356:Lipid Metabolism; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects*; D058226:Plaque, Atherosclerotic / Q000235:genetics* / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D019010:Vascular Cell Adhesion Molecule-1 / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000975:Antioxidants; C090509:Icam1 protein, mouse; D011973:Receptors, LDL; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D003094:Collagen; D001663:Bilirubin
keywords: adhesion molecule; atherosclerosis; bilirubin; intercellular adhesion molecule 1; monocyte; vascular cell adhesion molecule 1; vascular endothelium