Inhibition of ischemia-induced angiogenesis by benzo[a]pyrene in a manner dependent on the aryl hydrocarbon receptor.

Abstract

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.

• Authors: Sahoko Ichihara, Yoshiji Yamada, Frank J Gonzalez, Tamie Nakajima, Toyoaki Murohara, Gaku Ichihara
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 381 Issue 1 Pg. 44-9 (Mar 27 2009) ISSN: 1090-2104 [Electronic] United States
• PMID: 19351592 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Arnt protein, mouse
• Carcinogens
• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• Interleukin-6
• Mt2 protein, mouse
• Receptors, Angiotensin
• Receptors, Aryl Hydrocarbon
• Vascular Endothelial Growth Factor A
• metallothionein-1, mouse
• Aryl Hydrocarbon Receptor Nuclear Translocator
• Benzo(a)pyrene
• Metallothionein
• Angiotensin I
• Cytochrome P-450 CYP1A1
• Receptors, Vascular Endothelial Growth Factor

Topics

• Angiotensin I (biosynthesis)
• Animals
• Aryl Hydrocarbon Receptor Nuclear Translocator (biosynthesis)
• Benzo(a)pyrene (toxicity)
• Carcinogens (toxicity)
• Cytochrome P-450 CYP1A1 (biosynthesis)
• Femoral Artery (physiopathology)
• Hypoxia-Inducible Factor 1, alpha Subunit (biosynthesis)
• Interleukin-6 (biosynthesis)
• Ischemia (physiopathology)
• Lower Extremity (blood supply)
• Male
• Metallothionein (biosynthesis)
• Mice
• Mice, Inbred Strains
• Neovascularization, Physiologic (drug effects)
• Receptors, Angiotensin (biosynthesis)
• Receptors, Aryl Hydrocarbon (agonists, genetics, physiology)
• Receptors, Vascular Endothelial Growth Factor (biosynthesis)
• Up-Regulation
• Vascular Endothelial Growth Factor A (biosynthesis)