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Circulation Research. 2001;89:753-762
doi: 10.1161/hh2101.099268
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(Circulation Research. 2001;89:753.)
© 2001 American Heart Association, Inc.


Reviews

Cytochrome P450 and Vascular Homeostasis

Ingrid Fleming

From the Institut für Kardiovaskuläre Physiologie, Klinikum der J.W.G.-Universität, Frankfurt am Main, Germany.

Correspondence to Dr Ingrid Fleming, Institut für Kardiovaskuläre Physiologie, Klinikum der J.W.G.-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany. E-mail fleming{at}em.uni-frankfurt.de

Abstract

Since the initial reports that renal cytochrome P450 (CYP) enzymes can metabolize arachidonic acid to substances which affect arterial tone, it has become increasingly clear that CYP enzymes expressed within the cardiovascular system play a crucial role in the modulation of vascular homeostasis. There is strong evidence suggesting that the activation of a CYP epoxygenase in endothelial cells is an essential step in nitric oxide and prostacyclin-independent vasodilatation of several vascular beds, particularly in the heart and kidney. A smooth muscle CYP {omega}-hydroxylase, on the other hand, generates a vasoconstrictor eicosanoid that is central to the myogenic response. Moreover, CYP epoxygenase and {omega}-hydroxylase products, as well as CYP-derived reactive oxygen species, are intracellular signal transduction molecules involved in several signaling cascades affecting numerous cellular processes, including vascular cell proliferation and angiogenesis. This review summarizes the vascular effects of epoxyeicosatrienoic acids and 20-hydroxyeicosatetraenoic acid, both of which are CYP-derived metabolites of arachidonic acid, endogenously generated within endothelial and vascular smooth muscle cells. Although the link between CYP expression/activity and cardiovascular disease is currently tentative, the evidence being accumulated to suggest that CYP pathways are altered in animal models of hypertension and atherosclerosis can no longer be ignored. The development of selective pharmacological tools is, however, a prerequisite for the analysis of the involvement of specific CYP isoforms in the regulation of vascular homeostasis in human subjects.


Key Words: endothelial dysfunction • endothelium-derived hyperpolarizing factor • epoxyeicosatrienoic acids • free radicals • 20-hydroxyeicosatetraenoic acid




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T. Allen, M. Iftinca, W. C Cole, and F. Plane
Smooth muscle membrane potential modulates endothelium-dependent relaxation of rat basilar artery via myo-endothelial gap junctions
J. Physiol., December 15, 2002; 545(3): 975 - 986.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Heart Circ. Physiol.Home page
X. Fang, N. L. Weintraub, C. L. Oltman, L. L. Stoll, T. L. Kaduce, S. Harmon, K. C. Dellsperger, C. Morisseau, B. D. Hammock, and A. A. Spector
Human coronary endothelial cells convert 14,15-EET to a biologically active chain-shortened epoxide
Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2306 - H2314.
[Abstract] [Full Text] [PDF]


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Circ. Res.Home page
Y. Liu, K. Terata, Q. Chai, H. Li, L. H. Kleinman, and D. D. Gutterman
Peroxynitrite Inhibits Ca2+-Activated K+ Channel Activity in Smooth Muscle of Human Coronary Arterioles
Circ. Res., November 29, 2002; 91(11): 1070 - 1076.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Heart Circ. Physiol.Home page
H. L. Xu, R. A. Santizo, V. L. Baughman, and D. A. Pelligrino
ADP-induced pial arteriolar dilation in ovariectomized rats involves gap junctional communication
Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H1082 - H1091.
[Abstract] [Full Text] [PDF]


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J. Physiol.Home page
H. C Parkington, J. A. M Chow, R. G Evans, H. A Coleman, and M. Tare
Role for endothelium-derived hyperpolarizing factor in vascular tone in rat mesenteric and hindlimb circulations in vivo
J. Physiol., August 1, 2002; 542(3): 929 - 937.
[Abstract] [Full Text] [PDF]


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Circ. Res.Home page
I. Fleming
To Move or Not To Move?: Cytochrome P450 Products and Cell Migration
Circ. Res., May 17, 2002; 90(9): 936 - 938.
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Circ. Res.Home page
J. Sun, X. Sui, J. A. Bradbury, D. C. Zeldin, M. S. Conte, and J. K. Liao
Inhibition of Vascular Smooth Muscle Cell Migration by Cytochrome P450 Epoxygenase-Derived Eicosanoids
Circ. Res., May 17, 2002; 90(9): 1020 - 1027.
[Abstract] [Full Text] [PDF]


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J. Biol. Chem.Home page
M. Potente, U. R. Michaelis, B. Fisslthaler, R. Busse, and I. Fleming
Cytochrome P450 2C9-induced Endothelial Cell Proliferation Involves Induction of Mitogen-activated Protein (MAP) Kinase Phosphatase-1, Inhibition of the c-Jun N-terminal Kinase, and Up-regulation of Cyclin D1
J. Biol. Chem., May 3, 2002; 277(18): 15671 - 15676.
[Abstract] [Full Text] [PDF]


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Circ. Res.Home page
R. Popp, R. P. Brandes, G. Ott, R. Busse, and I. Fleming
Dynamic Modulation of Interendothelial Gap Junctional Communication by 11,12-Epoxyeicosatrienoic Acid
Circ. Res., April 19, 2002; 90(7): 800 - 806.
[Abstract] [Full Text] [PDF]


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Circ. Res.Home page
R. Popp, R. P. Brandes, G. Ott, R. Busse, and I. Fleming
Dynamic Modulation of Interendothelial Gap Junctional Communication by 11,12-Epoxyeicosatrienoic Acid
Circ. Res., April 19, 2002; 90(7): 800 - 806.
[Abstract] [Full Text] [PDF]