title: Bilirubin from heme oxygenase-1 attenuates vascular endothelial activation and dysfunction.
abstract: OBJECTIVE
  Heme oxygenase-1 (HO-1), the rate-limiting enzyme of heme degradation, has recently been considered to have protective roles against various pathophysiological conditions. Since we demonstrated that HO-1 overexpression inhibits atherosclerotic formation in animal models, we examined the effect of HO modulation on proinflammatory cytokine production, endothelial NO synthase (eNOS) expression, and endothelium-dependent vascular relaxation responses.
  
  
  RESULTS
  After HO-1 induction by heme arginate (HA), vascular endothelial cell cultures were exposed to oxidized low-density lipoprotein (oxLDL) or tumor necrosis factor-alpha (TNF-alpha). HA pretreatment significantly attenuated the production of vascular cell adhesion molecule-1, monocyte chemotactic protein-1, and macrophage colony-stimulating factor, suggesting that HO-1 induction attenuates proinflammatory responses. In addition, HO-1 overexpression also alleviated endothelial dysfunction as judged by restoration of attenuated eNOS expression after exposure to oxLDL and TNF-alpha. Importantly, impaired endothelium-dependent vascular relaxation responses in thoracic aortic rings from high-fat-fed LDL receptor knockout mice were also improved. These effects were observed by treatment with bilirubin not by carbon monoxide.
  
  
  CONCLUSIONS
  These results suggest that the antiatherogenic properties of HO-1 may be mediated predominantly through the action of bilirubin by inhibition of vascular endothelial activation and dysfunction in response to proinflammatory stresses.
authors.affiliation: First Department of Internal Medicine, Fukushima Medical University, Fukushima, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kawamura
authors.forename: Kazunobu
authors.initials: K
authors.lastname: Ishikawa
authors.forename: Youichiro
authors.initials: Y
authors.lastname: Wada
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kimura
authors.forename: Hayato
authors.initials: H
authors.lastname: Matsumoto
authors.forename: Takahide
authors.initials: T
authors.lastname: Kohro
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Itabe
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Kodama
authors.forename: Yukio
authors.initials: Y
authors.lastname: Maruyama
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology; D001013:Aorta, Thoracic / Q000201:enzymology / Q000378:metabolism; D001120:Arginine / Q000494:pharmacology; D001663:Bilirubin / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology*; D004790:Enzyme Induction / Q000187:drug effects / Q000502:physiology; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D006418:Heme / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism* / Q000502:physiology; D051547:Heme Oxygenase-1; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000201:enzymology / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014664:Vasodilation / Q000502:physiology
chemical_list: D008077:Lipoproteins, LDL; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; C099252:oxidized low density lipoprotein; D006418:Heme; D001120:Arginine; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C048849:heme arginate; D001663:Bilirubin