Cytochrome P450 eicosanoids and cerebral vascular function

John D. Imig; Alexis N. Simpkins; Marija Renic; David R. Harder

doi:10.1017/S1462399411001773

Cytochrome P450 eicosanoids and cerebral vascular function

Published online by Cambridge University Press: 01 March 2011

Marija Renic and

John D. Imig*: Affiliation:
Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA. Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, WI, USA.
Alexis N. Simpkins: Affiliation:
Medical College of Georgia, Augusta, GA, USA.
Marija Renic: Affiliation:
Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, WI, USA.
David R. Harder: Affiliation:
Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, WI, USA. Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA.
*: *Corresponding author: John D. Imig, Department of Pharmacology and Toxicology, Cardiovascular Research Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. E-mail: [email protected]

Article contents

Abstract
References

Get access

Rights & Permissions

Abstract

The eicosanoids 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs), which are generated from the metabolism of arachidonic acid by cytochrome P450 (CYP) enzymes, possess a wide array of biological actions, including the regulation of blood flow to organs. 20-HETE and EETs are generated in various cell types in the brain and cerebral blood vessels, and contribute significantly to cerebral blood flow autoregulation and the coupling of regional brain blood flow to neuronal activity (neurovascular coupling). Investigations are beginning to unravel the molecular and cellular mechanisms by which these CYP eicosanoids regulate cerebral vascular function and the changes that occur in pathological states. Intriguingly, 20-HETE and the soluble epoxide hydrolase (sEH) enzyme that regulates EET levels have been explored as molecular therapeutic targets for cerebral vascular diseases. Inhibition of 20-HETE, or increasing EET levels by inhibiting the sEH enzyme, decreases cerebral damage following stroke. The improved outcome following cerebral ischaemia is a consequence of improving cerebral vascular structure or function and protecting neurons from cell death. Thus, the CYP eicosanoids are key regulators of cerebral vascular function and novel therapeutic targets for cardiovascular diseases and neurological disorders.

Type: Review Article
Information: Expert Reviews in Molecular Medicine , Volume 13 , March 2011 , e7

DOI: https://doi.org/10.1017/S1462399411001773 [Opens in a new window]
Copyright: Copyright © Cambridge University Press 2011

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1Faraci, F.M. and Heistad, D.D. (1998) Regulation of the cerebral circulation: role of endothelium and potassium channels. Physiological Reviews 78, 53-97CrossRef Google Scholar PubMed

2Harder, D.R. et al. (1997) Cytochrome P450 metabolites of arachidonic acid as intracellular signaling molecules in vascular tissue. Journal of Vascular Research 34, 237-243CrossRef Google Scholar PubMed

3Girouard, H. and Iadecola, C. (2006) Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease. Journal of Applied Physiology 100, 328-335CrossRef Google Scholar PubMed

4Krizanac-Bengez, L., Mayberg, M.R. and Janigro, D. (2004) The cerebral vasculature as a therapeutic target for neurological disorders and the role of shear stress in vascular homeostatis and pathophysiology. Neurological Research 26, 846-853CrossRef Google Scholar PubMed

5Filosa, J.A. and Blanco, V.M. (2007) Neurovascular coupling in the mammalian brain. Experimental Physiology 92, 641-646CrossRef Google Scholar PubMed

6Koehler, R.C., Gebremedhin, D. and Harder, D.R. (2006) Role of astrocytes in cerebrovascular regulation. Journal of Applied Physiology 100, 307-317CrossRef Google Scholar PubMed

7Koehler, R.C., Roman, R.J. and Harder, D.R. (2009) Astrocytes and the regulation of cerebral blood flow. Trends in Neurosciences 32, 160-169CrossRef Google Scholar PubMed

8Strandgaard, S. and Paulson, O.B. (1984) Cerebral autoregulation. Stroke 15, 413-416CrossRef Google Scholar PubMed

9Johnson, P.C. (1991) The myogenic response. News in Physiological Sciences 6, 41-42Google Scholar

10Roman, R.J. (2003) Autoregulation of blood flow. In Hypertension Primer (Izzo, J.L. and Black, H.R., eds), pp. 114-117, Lippincott Williams & Wilkins, Philadelphia, PA, Chapter 39Google Scholar

11Dunn, K.M. and Nelson, M.T. (2010) Potassium channels and neurovascular coupling. Circulation Journal 74, 608-616CrossRef Google Scholar PubMed

12Dunn, K.M. et al. (2008) Elevated production of 20-HETE in the cerebral vasculature contributes to severity of ischemic stroke and oxidative stress in spontaneously hypertensive rats. American Journal of Physiology. Heart and Circulatory Physiology 295, H2455-H2465CrossRef Google Scholar PubMed

13Harder, D.R. et al. (1994) Formation and action of a P-450 4A metabolite of arachidonic acid in cat cerebral microvessels. American Journal of Physiology 266, H2098-H2107Google Scholar PubMed

14Roman, R.J. (2002) P-450 metabolites of arachidonic acid in the control of cardiovascular function. Physiological Reviews 82, 131-185CrossRef Google Scholar

15Iliff, J.J. et al. (2010) Epoxyeicosanoid signaling in CNS function and disease. Prostaglandins and Other Lipid Mediators 91, 68-84CrossRef Google Scholar

16Liu, X. et al. (2008) Interaction of nitric oxide, 20-HETE, and EETs during functional hyperemia in whisker barrel cortex. American Journal of Physiology. Heart and Circulatory Physiology 295, H619-H631CrossRef Google Scholar PubMed

17Imig, J.D., Falck, J.R. and Inscho, E.W. (1999) Contribution of cytochrome P450 epoxygenase and hydroxylase pathways to afferent arteriolar autoregulatory responsiveness. British Journal of Pharmacology 127, 1399-1405CrossRef Google Scholar PubMed

18Gebremedhin, D. et al. (2000) Production of 20-HETE and its role in autoregulation of cerebral blood flow. Circulation Research 87, 60-65CrossRef Google Scholar PubMed

19Dickinson, C.J. (2001) Why are strokes related to hypertension? Classic studies and hypotheses revisited. Journal of Hypertension 19, 1515-1521CrossRef Google Scholar PubMed

20Jennings, J.R. et al. (2005) Reduced cerebral blood flow response and compensation among patients with untreated hypertension. Neurology 64, 1358-1365CrossRef Google Scholar PubMed

21Niwa, K. et al. (2002) Cerebrovascular autoregulation is profoundly impaired in mice overexpressing amyloid precursor protein. American Journal of Physiology. Heart and Circulatory Physiology 283, H315-H323CrossRef Google Scholar PubMed

22Niwa, K. et al. (2000) Abeta 1-40-related reduction in functional hyperemia in mouse neocortex during somatosensory activation. Proceedings of the National Academy of Sciences of the United States of America 97, 9735-9740CrossRef Google Scholar PubMed

23Dietrich, H.H., Kajita, Y. and Dacey, R.G. Jr. (1996) Local and conducted vasomotor responses in isolated rat cerebral arterioles. American Journal of Physiology. Heart and Circulatory Physiology 271, H1109-H1116CrossRef Google Scholar PubMed

24Iadecola, C. (2004) Neurovascular regulation in the normal brain and in Alzheimer's disease. Nature Reviews. Neuroscience 5, 347-360CrossRef Google Scholar PubMed

25Goldstein, L.B. et al. (2001) Primary prevention of ischemic stroke: a statement for healthcare professionals from the stroke council of the American Heart Association. Circulation 103, 163-182CrossRef Google Scholar PubMed

26Zweifler, R.M. (2003) Management of acute stroke. Southern Medical Journal 96, 380-385CrossRef Google Scholar PubMed

27Alberts, M.J. (2003) Update on the treatment and prevention of ischaemic stroke. Current Medical Research and Opinion 19, 438-441CrossRef Google Scholar PubMed

28Sudhahar, V., Shaw, S. and Imig, J.D. (2010) Epoxyeicosatrienoic acid analogs and vascular function. Current Medical Chemistry 17, 1181-1190CrossRef Google Scholar PubMed

29Imig, J.D. (2010) Targeting epoxides for organ damage in hypertension. Journal of Cardiovascular Pharmacology 56, 329-335CrossRef Google Scholar PubMed

30Sodhi, K. et al. (2009) Epoxyeicosatrienoic acid agonist rescues the metabolic syndrome phenotype of HO-2-null mice. Journal of Pharmacology and Experimental Therapeutics 331, 906-916CrossRef Google Scholar PubMed

31Imig, J.D. et al. (2010) Development of epoxyeicosatrienoic acid analogs with in vivo anti-hypertensive actions. Frontiers in Vascular Physiology 1, 157Google Scholar PubMed

32Imig, J.D. and Hammock, B.D. (2009) Soluble epoxide hydrolase as a therapeutic target for cardiovascular diseases. Nature Reviews. Drug Discovery 8, 794-805CrossRef Google Scholar PubMed

33Fornage, M. et al. (2005) The soluble epoxide hydrolase gene harbors sequence variation associated with susceptibility to and protection from incident ischemic stroke. Human Molecular Genetics 14, 2829-2837CrossRef Google Scholar PubMed

34Koerner, I.P. et al. (2007) Polymorphisms in the human soluble epoxide hydrolase gene EPHX2 linked to neuronal survival after ischemic injury. Journal of Neuroscience 27, 4642-4649CrossRef Google Scholar PubMed

35Zhang, L. et al. (2008) genetic variation in cytochrome P450 2J2 and soluble epoxide hydrolase and risk of ischemic stroke in Chinese population. Pharmacogenetics and Genomics 18, 45-51CrossRef Google Scholar PubMed

36Fava, C. et al. (2010) Homozygosity for the EPHX2 K55R polymorphism increases the long-term risk of ischemic stroke in men: a study in Swedes. Pharmacogenetics and Genomics 20, 94-103CrossRef Google Scholar

37Gschwendtner, A. et al. (2008) Genetic variation in soluble epoxide hyrolase (EPHX2) is associated with an increased risk of ischemic stroke in white Europeans. Stroke 39, 1593-1596CrossRef Google Scholar

38Lee, J. et al. (2010) genetically reduced soluble epoxide hydrolase activity and risk of stroke and other cardiovascular disease. Stroke 41, 27-33CrossRef Google Scholar PubMed

39Dorrance, A.M. et al. (2005) An epoxide hydrolase inhibitor, 12-(3-adamantan-1-yl-ureido)dodecanoic acid (AUDA), reduces ischemic cerebral infarct size in stroke-prone spontaneously hypertensive rats. Journal of Cardiovascular Pharmacology 46, 842-848CrossRef Google Scholar

40Simpkins, A.N. et al. (2009) Soluble epoxide inhibition is protective against cerebral ischemia via vascular and neural rotection. American Journal of Pathology 174, 2086-2095CrossRef Google Scholar

41Zhang, W. et al. (2007) Soluble epoxide hydrolase: a novel therapeutic target in stroke. Journal of Cerebral Blood Flow and Metabolism 27, 1931-1940CrossRef Google Scholar PubMed

42Zhang, W. et al. (2008) Soluble epoxide hydrolase gene deletion is protective against experimental cerebral ischemia. Stroke 39, 2073-2078CrossRef Google Scholar PubMed

43Yamori, Y. (1984) Development of the spontantaneously hypertensive rat (SHR) and of various spontaneous rat models, and their implications. In Handbook of Hypertension, Vol. 4. Experimental and Genetic Models of Hypertension (de Jong, W., ed.), pp. 224-239, Elsevier, Amsterdam, New York, Oxford.Google Scholar

44Alkayed, N.J. et al. (2002) Neuroprotection and P450 2C11 upregulation after experimental transient ischemic attack. Stroke 33, 1677-1684CrossRef Google Scholar PubMed

45Liu, M. and Alkayed, N.J. (2005) Hypoxic preconditioning and tolerance via hypoxia inducible factor (HIF) 1alpha-linked induction of P450 2C11 epoxygenase in astrocytes. Journal of Cerebral Blood Flow and Metabolism 25, 939-948CrossRef Google Scholar PubMed

46Fleming, I. (2007) Epoxyeicosatrienoic acids, cell signaling and angiogenesis. Prostaglandins and Other Lipid Mediators 82, 60-67CrossRef Google Scholar PubMed

47Yang, B. et al. (2001) Overexpression of cytochrome P450 CYP2J2 protects against hypoxia-reoxygenation injury in cultured bovine aortic endothelial cells. Molecular Pharmacology 60, 310-320CrossRef Google Scholar PubMed

48Dickens, M. et al. (1997) A cytoplasmic inhibitor of the JNK signal transduction pathway. Science 277, 693-696CrossRef Google Scholar PubMed

49Kim, I.J. et al. (1999) Molecular cloning of multiple splicing variants of JIP-1 preferentially expressed in brain. Journal of Neurochemistry 72, 1335-1343CrossRef Google Scholar PubMed

50Whitmarsh, A.J. et al. (1998) A mammalian scaffold complex that selectively mediates MAP kinase activation. Science 281, 1671-1674CrossRef Google Scholar PubMed

51Becker, A.J. et al. (1999) Differential regulation of apoptosis-related genes in resistant and vulnerable subfields of the rat epileptic hippocampus. Brain Research. Molecular Brain Research 67, 172-176CrossRef Google Scholar PubMed

52Fu, Z. et al. (2008) Haplotype-based case study of human CYP4A11 gene and cerebral infarction in Japanese subject. Endocrine 33, 215-222CrossRef Google Scholar PubMed

53Fu, Z. et al. (2008) A haplotype of the CYP4F2 gene is associated with cerebral infarction in Japanese men. American Journal of Hypertension 21, 1216-1223CrossRef Google Scholar PubMed

54Ding, H. et al. (2010) Association of common variants of CYP4A11 and CYP4F2 with stroke in the Han Chinese population. Pharmacogenetics and Genomics 20, 187-194CrossRef Google Scholar PubMed

55Miyata, N. et al. (2005) Beneficial effects of a new 20-hydroxyeicosatetraenoic acid synthesis inhibitor, TS-011 [N-(3-chloro-4-morpholin-4-yl) phenyl-N'-hydroxyimido formamide], on hemorrhagic and ischemic stroke. Journal of Pharmacology and Experimental Therapeutics 314, 77-85CrossRef Google Scholar PubMed

56Renic, M. et al. (2009) Effect of 20-HETE inhibition on infarct volume and cerebral blood flow after transient middle cerebral artery occlusion. Journal of Cerebral Blood Flow and Metabolism 29, 629-639CrossRef Google Scholar PubMed

57Marumo, T. et al. (2010) The inhibitor of 20-HETE synthesis, TS-011, improves cerebral microcirculatory autoregulation impaired by middle cerebral artery occlusion in mice. British Journal of Pharmacology 161, 1391-1402CrossRef Google Scholar PubMed

58Tanaka, Y. et al. (2007) Continuous inhibition of 20-HETE synthesis by TS-011 improves neurological and functional outcomes after transient focal cerebral ischemia in rats. Neuroscience Research 59, 475-480CrossRef Google Scholar PubMed

59Poloyac, S.M. et al. (2006) Protective effect of the 20-HETE inhibitor HET0016 on brain damage after temporary focal ischemia. Journal of Cerebral Blood Flow and Metabolism 26, 1551-1561CrossRef Google Scholar PubMed

60De Mey, J.G. et al. (2005) Toward functional genomics of flow-induced outward remodeling of resistance arteries. American Journal of Physiology. Heart and Circulatory Physiology 288, H1022-H1027CrossRef Google Scholar PubMed

61Berk, B.C. (2001) Vascular smooth muscle growth: autocrine growth mechanisms. Physiological Reviews 81, 999-1030CrossRef Google Scholar PubMed

62Glasglov, S. et al. (1987) Compensatory enlargement of human atherosclerotic coronary arteries. New England Journal of Medicine 316, 1371-1375Google Scholar

63Korshunov, V.A., Schwartz, S.M. and Berk, B.C. (2007) Vascular remodeling: hemodynamic and biochemical mechanisms underlying Glagov's phenomenon. Arteriosclerosis, Thrombosis, and Vascular Biology 27, 1772–1728CrossRef Google Scholar PubMed

64Integan, H.D. and Schiffrin, E.L. (2001) Vascular remodeling in hypertension: roles of apoptosis, inflammation, and fibrosis. Hypertension 38, 581-587CrossRef Google Scholar

65Toda, N., Okunishi, H. and Miyazaki, M. (1982) Length-passive tension relationships in cerebral and peripheral arteies isolated from spontaneously hypertensive and normotensive rats. Japanese Circulation Journal 46, 1088-1094CrossRef Google Scholar

66Buus, C.L. et al. (2001) Smooth muscle cell changes during flow-related remodeling of rat mesenteric resistance arteries. Circulation Research 89, 180-186CrossRef Google Scholar PubMed

67Zargham, R. (2008) Preventing restenosis after angioplasty: a multistage approach. Clinical Science 114, 257-264CrossRef Google Scholar PubMed

68Przybyla-Zawislak, B.D. et al. (2003) Polymorphisms in human soluble epoxide hydrolase. Molecular Pharmacology 64, 482-490CrossRef Google Scholar PubMed

69Srivastava, P.K. et al. (2004) Polymorphisms in human soluble epoxide hydrolase: effects on enzyme activity, enzyme stability, and quaternary structure. Archives of Biochemistry and Biophysics. 427, 164-169CrossRef Google Scholar PubMed

70Lee, C.R. et al. (2006) Genetic variation in soluble epoxide hydrolase (EPHX2) and risk of coronary heart disease: The Atherosclerosis Risk in Communities (ARIC) study. Human Molecular Genetics 15, 1640-1649CrossRef Google Scholar PubMed

71Fornage, M. et al. (2004) Polymorphism of the soluble epoxide hydrolase is associated with coronary artery calcification in African-American subjects: the Coronary Artery Risk Development in Young Adults (CARDIA) study. Circulation 109, 335-339CrossRef Google Scholar PubMed

72Ng, V.Y. et al. (2006) Inhibition of smooth muscle proliferation by urea-based alkanoic acids via peroxisome proliferator-activated receptor alpha-dependent repression of cyclin D1. Arteriosclerosis, Thrombosis, and Vascular Biology 26, 2462-2468CrossRef Google Scholar PubMed

73Davis, B.B. et al. (2002) Inhibitors of soluble epoxide hydrolase attenuate vascular smooth muscle cell proliferation. Proceedings of the National Academy of Sciences of the United States of America 99, 2222-2227CrossRef Google Scholar PubMed

74Nieves, D. and Moreno, J.J. (2007) Epoxyeicosatrienoic acids induce growth inhibition and calpain/caspase-12 dependent apoptosis in PDGF cultured 3T6 fibroblast. Apoptosis 12, 1979-1988CrossRef Google Scholar PubMed

75Sun, J. et al. (2002) Inhibition of vascular smooth muscle cell migration by cytochrome p450 epoxygenase-derived eicosanoids. Circulation Research 90, 1020-1027CrossRef Google Scholar PubMed

76Zhao, X. et al. (2004) Soluble epoxide hydrolase inhibition protects the kidney from hypertension-induced damage. Journal of the American Society of Nephrology 15, 1244-1253Google Scholar PubMed

77Coyle, P. and Jokelainen, P.T. (1983) Differential outcome to middle cerebral artery occlusion in spontaneously hypertensive stroke-prone rats (SHRSP) and Wistar Kyoto (WKY) rats. Stroke 14, 605-611CrossRef Google Scholar PubMed

78Carswell, H.V. et al. (1999) Genetic and gender influences on sensitivity to focal cerebral ischemia in the stroke-prone spontaneously hypertensive rat. Hypertension 33, 681-685CrossRef Google Scholar PubMed

79Jesmin, S. et al. (2004) Characterization of regional cerebral blood flow and expression of angiogenic growth factors in the frontal cortex of juvenile male SHRSP and SHR. Brain Research 1030, 72-82CrossRef Google Scholar PubMed

80Coyle, P. and Heistad, D.D. (1991) Development of collaterals in the cerebral circulation. Blood Vessels 28, 183-189Google Scholar PubMed

81Zhang, C. and Harder, D.R. (2002) Cerebral capillary endothelial cell mitogenesis and morphogenesis induced by astrocytic epoxyeicosatrienoic acid. Stroke 33, 2957-2964CrossRef Google Scholar PubMed

82Munzenmaier, D.H. and Harder, D.R. (2000) Cerebral microvascular endothelial cell tube formation: role of astrocytic epoxyeicosatrienoic acid release. American Journal of Physiology. Heart and Circulatory Physiology. 278, H1163-H1167CrossRef Google Scholar PubMed

83Simpkins, A.N. et al. (2010) Soluble epoxide hydrolase inhibition modulates vascular remodeling. American Journal of Physiology. Heart and Circulatory Physiology 298, H795-H806CrossRef Google Scholar PubMed

84Stec, D.E. et al. (2007) 20-Hydroxyeicosatetraenoic acid (20-HETE) stimulates migration of vascular smooth muscle cells. Cell Physiology and Biochemistry 19, 121-128CrossRef Google Scholar PubMed

85Ljuca, F. and Drevensek, G. (2010) Endothelin-1 induced vascular smooth muscle cell proliferation is mediated by cytochrome P-450 arachidonic acid metabolites. Bosnian Journal of Basic Medical Sciences 10, 223-226CrossRef Google Scholar PubMed

86Liang, C.J. et al. (2008) 20-HETE inhibits the proliferation of vascular smooth muscle cells via transforming growth factor-beta. Journal of Lipid Research 49, 66-73CrossRef Google Scholar PubMed

87Guo, A.M. et al. (2009) 20-HETE can act as a nonhypoxic regulator of HIF-1alpha in human microvascular endothelial cells. American Journal of Physiology. Heart and Circulatory Physiology 297, H602-H613CrossRef Google Scholar PubMed

88Guo, A.M. et al. (2007) Activation of vascular endothelial growth factor through reactive oxygen species mediates 20-hydroxyeicosatetraenoic acid-induced endothelial cell proliferation. Journal of Pharmacology and Experimental Therapeutics 321, 18-27CrossRef Google Scholar PubMed

89Kozak, W. et al. (2000) Role of cytochrome P-450 in endogenous antipyresis. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 279, R455-R460CrossRef Google Scholar PubMed

90Terashvili, M. et al. (2008) Antinociception produced by 14,15-epoxyeicosatrienoic acid is mediated by the activation of beta-endorphin and met-enkephalin in the rat ventrolateral periaqueductal gray. Journal of Pharmacology and Experimental Therapeutics 326, 614-622CrossRef Google Scholar PubMed

91Inceoglu, B. et al. (2008) Soluble epoxide hydrolase and epoxyeicosatrienoic acids modulate two distinct analgesic pathways. Proceedings of the National Academy of Sciences of the United States of America 105, 18901-18906CrossRef Google Scholar PubMed

Article contents

Cytochrome P450 eicosanoids and cerebral vascular function

Abstract

Access options

References

References

Further reading, resources and contacts

This article has been cited by the following publications. This list is generated based on data provided by Crossref.

Article contents

Cytochrome P450 eicosanoids and cerebral vascular function

Abstract

Access options

References

References

Further reading, resources and contacts

Save article to Kindle

Save article to Dropbox

Save article to Google Drive

Reply to: Submit a response

Your details

You have entered the maximum number of contributors

Conflicting interests