Inhibition of ischemia-induced angiogenesis by benzo[a]pyrene in a manner dependent on the aryl hydrocarbon receptor.
We have investigated the effect of benzo[a]pyrene (B[a]P), a carcinogen of tobacco smoke and an agonist for the aryl hydrocarbon receptor (AHR), on hypoxia-induced angiogenesis. Ischemia was induced by femoral artery ligation in wild-type and AHR-null mice, and the animals were subjected to oral administration of B[a]P (125 mg/kg) once a week. Exposure to B[a]P up-regulated the expression of metallothionein in the ischemic hindlimb and markedly inhibited ischemia-induced angiogenesis in wild-type mice. The amounts of interleukin-6 and of vascular endothelial growth factor (VEGF) mRNA in the ischemic hindlimb of wild-type mice were reduced by exposure to B[a]P. These various effects of B[a]P were markedly attenuated in AHR-null mice. Our observations suggest that the loss of the inhibitory effect of B[a]P on ischemia-induced angiogenesis apparent in AHR-null mice may be attributable to maintenance of interleukin-6 expression and consequent promotion of angiogenesis through up-regulation of VEGF expression.
Department of Human Functional Genomics, Life Science Research Center, Mie University, 1577 Kurimamachiya-cho, Tsu, Mie 514-8507, Japan. saho@gene.mie-u.ac.jp
Sahoko
S
Ichihara
Yoshiji
Y
Yamada
Frank J
FJ
Gonzalez
Tamie
T
Nakajima
Toyoaki
T
Murohara
Gaku
G
Ichihara
D000803:Angiotensin I / Q000096:biosynthesis; D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000096:biosynthesis; D001564:Benzo(a)pyrene / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis; D005263:Femoral Artery / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D007511:Ischemia / Q000503:physiopathology*; D035002:Lower Extremity / Q000098:blood supply; D008297:Male; D008668:Metallothionein / Q000096:biosynthesis; D051379:Mice; D008815:Mice, Inbred Strains; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011945:Receptors, Angiotensin / Q000096:biosynthesis; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000096:biosynthesis; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
C497397:Arnt protein, mouse; D002273:Carcinogens; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015850:Interleukin-6; C491054:Mt2 protein, mouse; D011945:Receptors, Angiotensin; D018336:Receptors, Aryl Hydrocarbon; D042461:Vascular Endothelial Growth Factor A; C525355:metallothionein-1, mouse; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D001564:Benzo(a)pyrene; D008668:Metallothionein; D000803:Angiotensin I; D019363:Cytochrome P-450 CYP1A1; D040262:Receptors, Vascular Endothelial Growth Factor