Insulin resistance and endothelial dysfunction: Are epoxyeicosatrienoic acids the link?
Epoxyeicosatrienoic acids (EETs), the cytochrome P450 epoxygenase metabolites of arachidonic acid, are potent vasodilators and are believed to be the endothelium-derived hyperpolarizing factor in a number of vascular beds. In addition, EETs may play a role in the secretion and action of insulin and the metabolism of carbohydrates and lipids. Pharmacological manipulation of EETs may be a useful therapeutic approach for disease states such as hypertension, diabetes mellitus and the metabolic syndrome. EET mimetics and antagonists and drugs that increase EET synthesis or decrease their degradation are currently under investigation. The cellular mechanism of action of EETs appears to be complex and is being intensively studied by a number of investigators. In the present article, EET production, metabolism, isomerism and vasodilatory effects will be reviewed and potential mechanisms of action discussed. The role of EETs in insulin secretion and sensitivity and their implication in diabetes mellitus and the metabolic syndrome will also be reviewed. Drugs affecting EET bioavailability and action may be promising agents to use to treat hypertension/insulin resistance. The effects of these agents in experimental vascular disorders will also be discussed.
Mustafa
Sally
S
Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia.
Sharma
Vijay
V
McNeill
John H
JH
J Cardiovasc Pharmacol. 2007 May;49(5):306-15
17513950
Am J Physiol. 1998 Jan;274(1):H375-81
9458889
Br J Pharmacol. 1997 Aug;121(8):1579-88
9283690
Am J Pathol. 1990 Jun;136(6):1383-91
2356865
Am J Physiol Heart Circ Physiol. 2000 Aug;279(2):H857-62
10924087
Am J Med Sci. 1988 Apr;295(4):275-9
3364462
Hypertension. 2003 Oct;42(4):555-61
12953017
J Pharmacol Exp Ther. 2002 Nov;303(2):768-76
12388664
Am J Physiol Renal Physiol. 2005 Sep;289(3):F552-61
15798089
Stroke. 1996 May;27(5):971-9
8623121
Circ Res. 2005 Oct 28;97(9):908-15
16179585
Nature. 1999 Sep 30;401(6752):493-7
10519554
Biochem Biophys Res Commun. 2005 May 27;331(1):347-50
15845398
Curr Opin Nephrol Hypertens. 2002 Mar;11(2):177-83
11856910
FEBS Lett. 2002 Oct 30;531(1):2-6
12401193
Arch Biochem Biophys. 1988 Mar;261(2):257-63
3128168
Am J Physiol Heart Circ Physiol. 2005 Mar;288(3):H1344-51
15528233
J Vasc Res. 1998 Jul-Aug;35(4):274-84
9701712
J Physiol. 1997 Nov 1;504 ( Pt 3):537-43
9401962
Circulation. 2001 Apr 17;103(15):1992-8
11306529
Am J Physiol. 1991 Sep;261(3 Pt 2):H843-52
1887929
Am J Physiol Cell Physiol. 2007 Mar;292(3):C996-1012
16987999
Circulation. 1996 Dec 15;94(12):3341-7
8989149
Am J Physiol Heart Circ Physiol. 2006 Jan;290(1):H55-63
16113065
Cell Mol Life Sci. 2007 Nov;64(22):2985-93
17922229
J Biol Chem. 1993 Mar 25;268(9):6402-7
8454612
J Physiol. 1995 Jan 15;482 ( Pt 2):259-74
7536247
J Pharmacol Exp Ther. 2008 Mar;324(3):1019-27
18171909
Am J Physiol Heart Circ Physiol. 2008 Nov;295(5):H2068-78
18805895
Hypertension. 2007 Mar;49(3):590-6
17200437
Hypertension. 2002 Feb;39(2 Pt 2):609-13
11882617
J Biol Chem. 2002 Sep 20;277(38):35105-12
12124379
J Clin Invest. 1995 May;95(5):2150-60
7738183
Proc Natl Acad Sci U S A. 2007 May 22;104(21):9018-23
17495027
Endocrinology. 1997 Mar;138(3):1338-46
9048644
Arterioscler Thromb Vasc Biol. 2009 Jan;29(1):54-60
18927469
Hypertension. 2005 Oct;46(4):975-81
16157792
Arch Biochem Biophys. 1985 Oct;242(1):225-30
4051502
Hypertension. 2000 Aug;36(2):270-5
10948089
Am J Physiol. 1992 Aug;263(2 Pt 2):H519-25
1510149
Biochem Biophys Res Commun. 1992 Feb 14;182(3):1320-5
1540175
Am J Physiol Heart Circ Physiol. 2006 Feb;290(2):H491-9
16258029
Arch Biochem Biophys. 1990 Aug 1;280(2):346-51
2369126
Am J Physiol Regul Integr Comp Physiol. 2005 Jan;288(1):R188-96
15345471
Prostaglandins Other Lipid Mediat. 2007 Feb;83(1-2):50-61
17259072
Am J Physiol. 1996 May;270(5 Pt 2):F822-32
8928844
J Biol Chem. 1996 Feb 16;271(7):3460-8
8631948
J Pharmacol Exp Ther. 1998 Mar;284(3):966-73
9495856
FEBS Lett. 1990 Jul 30;268(1):227-30
2384159
Prostaglandins Other Lipid Mediat. 2003 Apr;71(1-2):33-42
12749592
Am J Physiol. 1998 Sep;275(3):L423-31
9728036
Am J Physiol Heart Circ Physiol. 2003 Jan;284(1):H337-49
12388250
Am J Physiol. 1993 Feb;264(2 Pt 2):H327-35
8447448
Am J Physiol Heart Circ Physiol. 2006 Jan;290(1):H64-71
16143653
Clin Sci (Lond). 2009 Jan;116(1):61-70
18459944
J Vasc Res. 2000 Sep-Oct;37(5):426-34
11025406
Circ Res. 2002 May 17;90(9):1028-36
12016270
J Pharmacol Exp Ther. 2009 Jan;328(1):231-9
18836067
Physiol Rev. 2002 Jan;82(1):131-85
11773611
Am J Physiol Heart Circ Physiol. 2001 Jun;280(6):H2470-7
11356600
Am J Physiol Renal Physiol. 2007 Oct;293(4):F1381-90
17699555
Bioorg Med Chem Lett. 2007 May 1;17(9):2634-8
17293113
J Biol Chem. 2001 May 4;276(18):14867-74
11278979
Prostaglandins Other Lipid Mediat. 2008 Dec;87(1-4):62-7
18812234
Arterioscler Thromb Vasc Biol. 2007 Dec;27(12):2612-8
17872452
Science. 1999 Aug 20;285(5431):1276-9
10455056
Circ Res. 1999 Aug 20;85(4):349-56
10455063
Biochem Biophys Res Commun. 1993 Feb 26;191(1):282-8
8447831
Curr Opin Clin Nutr Metab Care. 2007 Jul;10(4):523-30
17563474
Circ Res. 2008 Jan 4;102(1):59-67
17975109
J Cardiovasc Pharmacol. 2005 Dec;46(6):842-8
16306811
Am J Physiol Heart Circ Physiol. 2008 Nov;295(5):H1982-8
18790831
J Pharmacol Exp Ther. 1994 Dec;271(3):1427-33
7996455
Am J Physiol. 1990 Oct;259(4 Pt 2):H1171-7
2121049
Circ Res. 2005 Feb 18;96(3):376-83
15637296
J Biol Chem. 2007 Feb 2;282(5):2891-8
17135253
Circ Res. 2000 Nov 24;87(11):992-8
11090543
Circ Res. 1997 Jun;80(6):877-84
9168791
Am J Physiol. 1999 Sep;277(3):H1252-9
10484447
Arch Biochem Biophys. 1995 Jan 10;316(1):443-51
7840649
Circ Res. 2005 Dec 9;97(12):1270-9
16269659
J Biol Chem. 1993 Jun 15;268(17):12260-6
8509363
Br J Pharmacol. 1996 Apr;117(7):1600-6
8730760
J Lipid Mediat Cell Signal. 1997 Jul;16(3):155-69
9246605
Cardiovasc Res. 2008 Dec 1;80(3):445-52
18682435
Biochem Biophys Res Commun. 1983 Jul 29;114(2):743-9
6411091
Circulation. 2003 Feb 11;107(5):769-76
12578883
Am J Nephrol. 2008;28(4):598-606
18277067
Circulation. 2001 Mar 27;103(12):1702-8
11274000
J Am Coll Cardiol. 2006 Aug 1;48(3):508-15
16875977
Am J Physiol Heart Circ Physiol. 2002 Nov;283(5):H1936-42
12384472
J Biol Chem. 1991 Apr 25;266(12):7561-9
1902222
Biochem Biophys Res Commun. 1992 Feb 28;183(1):138-43
1543485
Diabetes. 2001 Apr;50(4):797-802
11289044
J Vet Pharmacol Ther. 2008 Feb;31(1):1-8
18177312
Am J Physiol Heart Circ Physiol. 2001 Oct;281(4):H1524-31
11557540
J Intern Med. 2007 Aug;262(2):173-83
17645585
Am J Physiol Heart Circ Physiol. 2008 May;294(5):H2363-70
18375719
Mol Pharmacol. 1999 Feb;55(2):288-95
9927620
Biochem Pharmacol. 2002 May 1;63(9):1599-608
12007563
Circ Res. 1996 Oct;79(4):784-93
8831502
Am J Physiol Heart Circ Physiol. 2001 Jun;280(6):H2430-40
11356595
Circ Res. 1998 Nov 2;83(9):932-9
9797342