Emerging mechanisms for growth and protection of the vasculature by cytochrome P450-derived products of arachidonic acid and other eicosanoids.
Arachidonic acid (AA) is an essential fatty acid that is metabolized by cyclooxygenase (COX), lipoxygenase (LOX) or cytochrome P450 (CYP) enzymes to generate eicosanoids which in turn mediate a number of biological activities including regulation of angiogenesis. While much information on the effects of COX and LOX products is known, the physiological relevance of the CYP-derived products of AA are less well understood. CYP enzymes are highly expressed in the liver and kidney, but have also been detected at lower levels in the brain, heart and vasculature. A number of these enzymes, including members of the CYP 4 family, predominantly catalyze conversion of AA to 20-hydroxyeicosatetraenoic acid (20-HETE) while the CYP epoxygenases generate mainly epoxyeicosatrienoic acids (EETs). This review will focus on the emerging roles of inhibitors of eicosanoid production with emphasis on the CYP pathways, in the regulation of angiogenesis and tumor growth. We also discuss current observations describing the protective effects of EETs for survival of the endothelium.
Medhora
Meetha
M
Division of Pulmonary and Critical Care, Department of Medicine, Medical College of Wisconsin, 8701, Watertown Plank Road, Milwaukee, WI 53226, USA. medhoram@mcw.edu
Dhanasekaran
Anuradha
A
Gruenloh
Stephanie K
SK
Dunn
Laurel K
LK
Gabrilovich
Michael
M
Falck
John R
JR
Harder
David R
DR
Jacobs
Elizabeth R
ER
Pratt
Phillip F
PF
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D000199:Actins / Q000187:drug effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001092:Arachidonate 12-Lipoxygenase / Q000502:physiology; D016718:Arachidonic Acid / Q000378:metabolism* / Q000494:pharmacology; D042926:Cytochrome P-450 CYP4A / Q000502:physiology; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D015777:Eicosanoids / Q000494:pharmacology*; D004852:Epoxy Compounds / Q000494:pharmacology; D006801:Humans; D007668:Kidney / Q000502:physiology; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic / Q000187:drug effects*
D000199:Actins; D015777:Eicosanoids; D004852:Epoxy Compounds; D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System; D001092:Arachidonate 12-Lipoxygenase; D042926:Cytochrome P-450 CYP4A; D015126:8,11,14-Eicosatrienoic Acid