Inhibitors of cytochrome P450 4A suppress angiogenic responses.
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 micromol/L and 20 microg, 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 microg) 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.
Chen
Ping
P
Eye Care Services, Henry Ford Health System, One Ford Place, 4 D, Detroit, MI 48202-3450, USA.
Guo
Meng
M
Wygle
Dana
D
Edwards
Paul A
PA
Falck
John R
JR
Roman
Richard J
RJ
Scicli
A Guillermo
AG
D000577:Amides / Q000494:pharmacology; D000578:Amidines / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured / Q000378:metabolism; D003315:Cornea / Q000098:blood supply / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D042926:Cytochrome P-450 CYP4A / Q000037:antagonists & inhibitors*; D018076:DNA, Complementary / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology; D008297:Male; D008934:Mitogens / Q000378:metabolism; D009389:Neovascularization, Pathologic; D016133:Polymerase Chain Reaction; D011108:Polymers / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013450:Sulfones / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C494665:20-hydroxyeicosa-5(Z),14(Z)-dienoic acid; D000577:Amides; D000578:Amidines; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; C000708209:HET0016; D006893:Hydroxyeicosatetraenoic Acids; D008934:Mitogens; D011108:Polymers; D012333:RNA, Messenger; D013450:Sulfones; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; C117975:DDMS; D042926:Cytochrome P-450 CYP4A