Inhibitors of cytochrome P450 4A suppress angiogenic responses

Ping Chen, Meng Guo, Dana Wygle, Paul A. Edwards, J R Falck, Richard J. Roman, A. Guillermo Scicli

Research output: Contribution to journalArticle

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Abstract

Cytochrome P450 enzymes of the 4A family (CYP4A) convert arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE) in blood vessels of several vascular beds. The present study examined the effects of inhibiting the formation of 20-HETE with N-hydroxy-N′-(4-butyl-2-methylphenol) formamidine (HET0016) on the mitogenic response of vascular endothelial growth factor (VEGF) in human umbilical vein endothelial cells (HUVECs) in vitro, and on growth factor-induced angiogenesis in the cornea of rats in vivo. HET0016 (10 μmol/L and 20 μg, respectively) abolished the mitogenic response to VEGf in HUVECs and the angiogenic response to VEGF, basic fibroblast growth factor, and epidermal growth factor in vivo by 80 to 90% (P < 0.001). Dibromododecenyl methylsulfonimide (DDMS), a structurally and mechanistically different inhibitor of 20-HETE synthesis, also abolished angiogenic responses when tested with VEGF. Additionally, administration of the stable 20-HETE agonist, 20-hydroxyeicosa-6(Z) 15(Z)-dienoic acid (WIT003) induced mitogenesis in HUVECs and angiogenesis in the rat cornea in vivo. We studied the ability of HET0016 to alter the angiogenic response in the rat cornea to human glioblastoma cancer cells (U251). When administered locally into the cornea, HET0016 (20 μg) reduced the angiogenic response to U251 cancer cells by 70%. These results suggest that a product of CYP4A product, possibly 20-HETE, plays a critical role in the regulation of angiogenesis and may provide a useful target for reduction of pathological angiogenesis.

Original languageEnglish (US)
Pages (from-to)615-624
Number of pages10
JournalAmerican Journal of Pathology
Volume166
Issue number2
StatePublished - Feb 2005

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Cytochrome P-450 Enzyme System
Cornea
Vascular Endothelial Growth Factor A
Human Umbilical Vein Endothelial Cells
Blood Vessels
Pathologic Neovascularization
Fibroblast Growth Factor 2
Glioblastoma
Epidermal Growth Factor
Arachidonic Acid
Neoplasms
Intercellular Signaling Peptides and Proteins
20-hydroxy-5,8,11,14-eicosatetraenoic acid

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Chen, P., Guo, M., Wygle, D., Edwards, P. A., Falck, J. R., Roman, R. J., & Scicli, A. G. (2005). Inhibitors of cytochrome P450 4A suppress angiogenic responses. American Journal of Pathology, 166(2), 615-624.

Inhibitors of cytochrome P450 4A suppress angiogenic responses. / Chen, Ping; Guo, Meng; Wygle, Dana; Edwards, Paul A.; Falck, J R; Roman, Richard J.; Scicli, A. Guillermo.

In: American Journal of Pathology, Vol. 166, No. 2, 02.2005, p. 615-624.

Research output: Contribution to journalArticle

Chen, P, Guo, M, Wygle, D, Edwards, PA, Falck, JR, Roman, RJ & Scicli, AG 2005, 'Inhibitors of cytochrome P450 4A suppress angiogenic responses', American Journal of Pathology, vol. 166, no. 2, pp. 615-624.
Chen P, Guo M, Wygle D, Edwards PA, Falck JR, Roman RJ et al. Inhibitors of cytochrome P450 4A suppress angiogenic responses. American Journal of Pathology. 2005 Feb;166(2):615-624.
Chen, Ping ; Guo, Meng ; Wygle, Dana ; Edwards, Paul A. ; Falck, J R ; Roman, Richard J. ; Scicli, A. Guillermo. / Inhibitors of cytochrome P450 4A suppress angiogenic responses. In: American Journal of Pathology. 2005 ; Vol. 166, No. 2. pp. 615-624.
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