How to Cite
გონგაძე ნ. G. N., გაბუნია ლ. G. L., მირზიაშვილი მ. M. M., გვიშიანი მ. G. M., & არჩვაძე ა. A. A. (2019). SOLUBLE EPOXIDE HYDROLASE AS A NEW TARGET FOR THERAPEUTIC INTERVENTION. Collection of Scientific Works of Tbilisi State Medical University, 49, 34–36. https://doi.org/10.52340/csw.2015.49.0.34-36
Abstract
Soluble epoxide hydrolase (sEH) – a bifunctional homodimeric enzyme located in both cytosol and peroxisomes (2, 23, 24) was identified in plants and mammals (19). sEH facilitates the conversion of epoxyeicosatrienoic acids (EETs) to the biologically less active dihydroxyeicosatrienoic acids (DHETs). Unlike prostaglandins, the EETs and DHETS can be incorporated into phospholipids, which then act as storage sites (10). The sEH is thought to take part largely in the metabolism of arachidonic, linoleic and other fatty acid epoxides, endogenous chemical mediators playing an important role in blood pressure regulation and inflammation (20, 21). It has been shown that inhibition of sEH by trans-4[4(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB) may lead to elevation of EETs level which in turn could elicit various beneficial biological effects in different conditions, such as hypertension, pulmonary diseases, diabetes, atherosclerosis, inflammation etc (9, 10). It was established that EETs are synthesized in endothelial cells and may lead to vasodilation by activating the smooth muscle large conductance Ca 2+ activated K channels, resulting in smooth muscle cell hyperpolarization in a number of vascular beds (3, 14).
References
1. Ai D., Pang W., Li N., Xu M. et al. Soluble epoxide hydrolase plays essential role in angiotensin II-induced cardiac hypertrophy. Proc. Nat. Acad. Sci. USA, 2009, 106:564-569.
2. Davis B.B., Thompson D. A., Howard L. L.Morisseau C., Hammock B. D. Inhibitors of soluble epoxide hydrolase attenuate vascular smooth muscle cell proliferation. www.pnas.org/cg;/do;/10.10.73.phas.261710799
3. Dimitripolou C., West L., Field M. B., White R. E., Reddy L. M., Falck R., Imig D. Protein phosphatase 2A and Ca 2+ -activated K channels contribute to 11,12-epoxyeicosatrienoic acid analog mediated mesenteric arterial relaxation. J. Prostaglandins and other lipid mediators. 2007, 83:50-61.
4. Dorrance A. M., Rupp N., Pollock D. M., Newman J. N., Hamock B. D., Imig D. An epoxide hydrolase inhibitor, 12-(3-adamantan-1yl-ureido) dodecanoic acid (AUDA) reduces ischemic cerebral infarct size in stroke-prone spontaneously hypertensive rats. J. Cardiovasc. Pharmacol. 2005, 46:842-848.
5. Fleming I. Cytochrome P450 and vascular homeostasis. J. Circ. Res. 2001, 89:753-762.
6. Fornage M., Hinojos C. A., Nurowska B. W. et al. Polymorphism in soluble epoxide hydrolase and blood pressure in spontaneously hypertensive rats. J. Hypertension. 2002, 40:485-490.
7. Honetschlagerova Z., Vanourkova Z., Sporkova A., Kramer H. J. et al. Renal mechanisms contributing to the antihypertensive action of soluble epoxide hydrolase inhibition in Ren-2-transgenic rats with inducible hypertension. J. Physiol. 2010, 589:207-219.
8. Imig D. Targeting epoxides for organ damage in hypertension. J. Cardiovasc. pharmacol 2010. 56:329-335.
9. Imig D., Hammock B. D. Soluble epoxide hydrolase as a therapeutic target for cardiovascular diseases. J. Nat. Rev. Drug. Discov. 2009, 8:794-805.
10. Imig J. D. Epoxides and soluble epoxide hydrolase in cardiovascular physiology. J. Physiol. Rev. 2012, 92: 101-130.
11. Imig D., Simpkins A. N., Renic M., Harder D. K. Cytochrome p-450 eicosanoids and cerebral vascular function. Expert Rev. Mol. Med. 2011. 13:17.
12. Imig D., Zhac X., Zaharis C. Z., Olearczyk J. I., Pollock D. M. et al. An orally active epoxide hydrolase inhibitor lowers blood pressure and provides renal protection in salt sensitive hypertension. J. Hypertension. 2011. 19: 983-992.
13. Koerner I. P., Jacks R., Debarber A. E., Koop D., Mao P., Grant D. F., Alkayed N. J. Polymorphisms in the human soluble epoxide hydrolase gene EPHX2 linked to neuronal survival after ischemic injury. J. Neurosci 207, 27:4642-4649.
14. Larsen B. T., Miura H., Hatoum O. A., Campbell W. B., Hammock B. D., et al. Epoxyeicosatrienoic and dihydroxyicosatrienoic acids dilate human coronary arterioles via BK (Ca) channels implications for soluble epoxide hydrolase inhibition. Am. J. Physiol. Heart circ. Physiol. 2006, 290:H491-H499.
15. Li J., Caroll M. A., Chander P. N., Falck R., Sangras B., Sier C. T. Soluble epoxide hydrolase inhibitor, AUDA, prevents early salt-sensitive hypertension. Front. Biosci 2008, 13:3480-3487
16. Marino P. J. Soluble epoxide hydrolase, a target with multiple opportunities for cardiovascular drug discovery. Curr. Top. Med. Chem. 2009, 9:452-463.
17. Merkel M. J., Liu L., Cao Z., Packwood W., Young J. et al. Inhibition of soluble epoxide hydrolase preserves cardiomyocytes role of STAT3 Signaling. Am. J. Physiol. Heart Circ. Physiol. 2010, 298:H679-687.
18. Michaelis U. R., Fleiming J. From endothelium-derived hyperpolarizing factor (EDHF) and cell signaling pharmacol. Ther 2006, 111:584-595.
19. Morisseau C., Hammock B. D. Epoxide hydrolases mechanisms, inhibitor designs, and biological roles Annu. Rev. Pharmacol, Toxicol. 2005, 45:311-333.
20. Node K., Huo Y., Ruan X., Yang B. et al. Anti-inflammatory properties of cytochrome p-450 epoxygenasederived eicosanoids. J. Science 1999; 235:1276-1279.
21. Roman R. J. p-450 metabolites of arachidonic acid in the control of cardiovascular function. J. Physiol. Rev. 2002;82:131-185.
22. Simpkins A. N., Rudic R. D., Schreihofer D. S., Roy S., Manhiani M. et al. Soluble epoxide inhibition is protective against cerebral ischemia via vascular and neural protection. Am. J. Pathol. 2009. 174:2086-2095.
23. Schmelzer K. R., Kubala L., Newman J. A. et al. Soluble epoxide hydrolase is a therapeutic target for acute inflammation. Proc. Nat. Acad. Sci. USA. 2005, 102:9772-9777.
24. Spector A. A., Fang X., Snyder G. D., Weintraub N. L. Epoxyeicosatrienoic acids (EETs) metabolism and biochemical function. J. Prog. Lipid Res. 2004, 43:55-90.
25. Yang S., Lin L., Chen J. K., Lee C. R., Seubert S. M. et al. Cytochrome p-450 epoxygenases protect endothelial cells from apoptosis induced by tumor necrosis factor alpha via MAPK and PI3K/Akt signaling pathways. Am. J. physiol. Heart Circ. Physiol. 2007, 293:H142-H151
2. Davis B.B., Thompson D. A., Howard L. L.Morisseau C., Hammock B. D. Inhibitors of soluble epoxide hydrolase attenuate vascular smooth muscle cell proliferation. www.pnas.org/cg;/do;/10.10.73.phas.261710799
3. Dimitripolou C., West L., Field M. B., White R. E., Reddy L. M., Falck R., Imig D. Protein phosphatase 2A and Ca 2+ -activated K channels contribute to 11,12-epoxyeicosatrienoic acid analog mediated mesenteric arterial relaxation. J. Prostaglandins and other lipid mediators. 2007, 83:50-61.
4. Dorrance A. M., Rupp N., Pollock D. M., Newman J. N., Hamock B. D., Imig D. An epoxide hydrolase inhibitor, 12-(3-adamantan-1yl-ureido) dodecanoic acid (AUDA) reduces ischemic cerebral infarct size in stroke-prone spontaneously hypertensive rats. J. Cardiovasc. Pharmacol. 2005, 46:842-848.
5. Fleming I. Cytochrome P450 and vascular homeostasis. J. Circ. Res. 2001, 89:753-762.
6. Fornage M., Hinojos C. A., Nurowska B. W. et al. Polymorphism in soluble epoxide hydrolase and blood pressure in spontaneously hypertensive rats. J. Hypertension. 2002, 40:485-490.
7. Honetschlagerova Z., Vanourkova Z., Sporkova A., Kramer H. J. et al. Renal mechanisms contributing to the antihypertensive action of soluble epoxide hydrolase inhibition in Ren-2-transgenic rats with inducible hypertension. J. Physiol. 2010, 589:207-219.
8. Imig D. Targeting epoxides for organ damage in hypertension. J. Cardiovasc. pharmacol 2010. 56:329-335.
9. Imig D., Hammock B. D. Soluble epoxide hydrolase as a therapeutic target for cardiovascular diseases. J. Nat. Rev. Drug. Discov. 2009, 8:794-805.
10. Imig J. D. Epoxides and soluble epoxide hydrolase in cardiovascular physiology. J. Physiol. Rev. 2012, 92: 101-130.
11. Imig D., Simpkins A. N., Renic M., Harder D. K. Cytochrome p-450 eicosanoids and cerebral vascular function. Expert Rev. Mol. Med. 2011. 13:17.
12. Imig D., Zhac X., Zaharis C. Z., Olearczyk J. I., Pollock D. M. et al. An orally active epoxide hydrolase inhibitor lowers blood pressure and provides renal protection in salt sensitive hypertension. J. Hypertension. 2011. 19: 983-992.
13. Koerner I. P., Jacks R., Debarber A. E., Koop D., Mao P., Grant D. F., Alkayed N. J. Polymorphisms in the human soluble epoxide hydrolase gene EPHX2 linked to neuronal survival after ischemic injury. J. Neurosci 207, 27:4642-4649.
14. Larsen B. T., Miura H., Hatoum O. A., Campbell W. B., Hammock B. D., et al. Epoxyeicosatrienoic and dihydroxyicosatrienoic acids dilate human coronary arterioles via BK (Ca) channels implications for soluble epoxide hydrolase inhibition. Am. J. Physiol. Heart circ. Physiol. 2006, 290:H491-H499.
15. Li J., Caroll M. A., Chander P. N., Falck R., Sangras B., Sier C. T. Soluble epoxide hydrolase inhibitor, AUDA, prevents early salt-sensitive hypertension. Front. Biosci 2008, 13:3480-3487
16. Marino P. J. Soluble epoxide hydrolase, a target with multiple opportunities for cardiovascular drug discovery. Curr. Top. Med. Chem. 2009, 9:452-463.
17. Merkel M. J., Liu L., Cao Z., Packwood W., Young J. et al. Inhibition of soluble epoxide hydrolase preserves cardiomyocytes role of STAT3 Signaling. Am. J. Physiol. Heart Circ. Physiol. 2010, 298:H679-687.
18. Michaelis U. R., Fleiming J. From endothelium-derived hyperpolarizing factor (EDHF) and cell signaling pharmacol. Ther 2006, 111:584-595.
19. Morisseau C., Hammock B. D. Epoxide hydrolases mechanisms, inhibitor designs, and biological roles Annu. Rev. Pharmacol, Toxicol. 2005, 45:311-333.
20. Node K., Huo Y., Ruan X., Yang B. et al. Anti-inflammatory properties of cytochrome p-450 epoxygenasederived eicosanoids. J. Science 1999; 235:1276-1279.
21. Roman R. J. p-450 metabolites of arachidonic acid in the control of cardiovascular function. J. Physiol. Rev. 2002;82:131-185.
22. Simpkins A. N., Rudic R. D., Schreihofer D. S., Roy S., Manhiani M. et al. Soluble epoxide inhibition is protective against cerebral ischemia via vascular and neural protection. Am. J. Pathol. 2009. 174:2086-2095.
23. Schmelzer K. R., Kubala L., Newman J. A. et al. Soluble epoxide hydrolase is a therapeutic target for acute inflammation. Proc. Nat. Acad. Sci. USA. 2005, 102:9772-9777.
24. Spector A. A., Fang X., Snyder G. D., Weintraub N. L. Epoxyeicosatrienoic acids (EETs) metabolism and biochemical function. J. Prog. Lipid Res. 2004, 43:55-90.
25. Yang S., Lin L., Chen J. K., Lee C. R., Seubert S. M. et al. Cytochrome p-450 epoxygenases protect endothelial cells from apoptosis induced by tumor necrosis factor alpha via MAPK and PI3K/Akt signaling pathways. Am. J. physiol. Heart Circ. Physiol. 2007, 293:H142-H151
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