Epoxyeicosatrienoic acids (EETs) are also known as epoxyeicosanoids that have renal and cardiovascular actions. These renal and cardiovascular actions can be regulated by soluble epoxide hydrolase (sEH) that degrades and inactivates EETs. Extensive animal hypertension studies have determined that vascular, epithelial transport, and anti-inflammatory actions of EETs lower blood pressure and decrease renal and cardiovascular disease progression. Human studies have also supported the notion that increasing EET levels in hypertension could be beneficial. Pharmacological and genetic approaches to increase epoxyeicosanoids in several animal models and humans have found improved endothelial vascular function, increased sodium excretion, and decreased inflammation to oppose hypertension and associated renal and cardiovascular complications. These compelling outcomes support the concept that increasing epoxyeicosanoids via sEH inhibitors or EET analogs could be a valuable hypertension treatment.

Department of Pharmacology and Toxicology Cardiovascular Center Medical College of Wisconsin Milwaukee WI USA

Zobrazit více v PubMed

BARRI YM: Hypertension and kidney diseases: a deadly connection. Curr Hypertens Rep 10: 39–45, 2008. PubMed

BATCHU SN, LEE SB, QADHI RS, CHAUDHARY KR, EL-SIKHRY H, KODELA R, FALCK JR, SEUBERT JM: Cardioprotective effect of a dual acting epoxyeicosatrienoic acid analogue towards ischaemia reperfusion injury. Br J Pharmacol 162: 897–907, 2011. PubMed PMC

BAYLIS C: Nitric oxide synthase derangements and hypertension in kidney disease. Curr Opin Nephrol Hypertens 21: 1–6, 2012. PubMed PMC

BELLIEN J, JOANNIDES R: Epoxyeicosatrienoic acid pathway in human health and diseases. J Cardiovasc Pharmacol 61: 188–196, 2013. PubMed

BELLIEN J, IACOB M, REMY-JOUET I, LUCAS D, MONTEIL C, GUTIERREZ L, VENDEVILLE C, DREANO Y, MERCIER A, THUILLEZ C, JOANNIDES R: Epoxyeicosatrienoic acids contribute with altered nitric oxide and endothelin-1 pathways to conduit artery endothelial dysfunction in essential hypertension. Circulation 125: 1266–1275, 2012. PubMed

CAMPBELL WB, GEBREMEDHIN D, PRATT PF, HARDER DR: Identification of epoxyeicosatrienoic acids as endothelium-derived hyperpolarizing factors. Circ Res 78: 415–423, 1996. PubMed

CAMPBELL WB, IMIG JD, SCHMITZ JM, FALCK JR: Orally active epoxyeicosatrienoic acid analogs. J Cardiovasc Pharmacol 70: 211–224, 2017. PubMed PMC

CAPDEVILA J, WANG W: Role of cytochrome P450 exoxygenase in regulating renal membrane transport and hypertension. Curr Opin Nephrol Hypertens 22: 163–169, 2013. PubMed PMC

CAPDEVILA JH, PIDKOVKA N, MEI S, GONG Y, FALCK JR, IMIG JD, HARRIS RC, WANG WH: The Cyp2c44 epoxygenase regulates epithelial sodium channel activity and the blood pressure responses to increased dietary salt. J Biol Chem 289: 4377–4386, 2014. PubMed PMC

ČERVENKA L, HUSKOVÁ Z, KOPKAN L, KIKERLOVÁ S, SEDLÁKOVÁ L, VAŇOURKOVÁ Z, ALÁNOVÁ P, KOLÁŘ F, HAMMOCK BD, HWANG SH, IMIG JD, FALCK JR, SADOWSKI J, KOMPANOWSKA-JEZIERSKA E, NECKÁŘ J: Two pharmacological epoxyeicosatrienoic acids-enhancing therapies effectively antihypertensive and reduce the severity of ischemic arrhythmias in rats with angiotensin II-dependent hypertension. J Hypertens 36: 1326–1341, 2018. PubMed PMC

CHOBANIAN AV et al.: Seventh Report of the Joint Committee on Prevention, Definition, Evaluation and Treatment of High Blood Pressure. Hypertension 42: 1206–1256, 2003. PubMed

DENG Y, EDIN ML, THEKEN KN, SCHUCK RN, FLAKE GP, KANNON MA, DEGRAFF LM, LIH FB, FOLEY J, BRADBURY JA, GRAVES JP, TOMER KB, FALCK JR, ZELDIN DC, LEE CR: Endothelial CYP epoxygenase overexpression and soluble epoxide hydrolase disruption attenuate acute vascular inflammatory responses in mice. FASEB J 25: 703–713, 2011. PubMed PMC

DREISBACH AW, JAPA S, SIGEL A, PARENTI MB, HESS AE, SRINOUANPRACHANH SL, RETTIE AE, KIM H, FARIN FM, HAMM LL, LERTORA JJ: The Prevalence of CYP2C8, 2C9, 2J2, and soluble epoxide hydrolase polymorphisms in African Americans with hypertension. Am J Hypertens 18: 1276–1281, 2005. PubMed

FALCK JR, KODURU SR, MOHAPATRA S, MANNE R, ATCHA R, MANTHATI VL, CAPDEVILA JH, CHRISTIAN S, IMIG JD, CAMPBELL WB. 14,15-Epoxyeicosa-5,8,11-trienoic acid (14,15-EET) surrogates: carboxylate modifications. J Med Chem 57: 6965–6972, 2014. PubMed PMC

FISSLTHALER B, POPP R, KISS L, POTENTE M, HARDER DR, FLEMING I, BUSSE R: Cytochrome P450 2C is an EDHF synthase in coronary arteries. Nature 401: 493–497, 1999. PubMed

HARRISON DG, GUZIK TJ, LOB HE, MADHUR MS, MARVAR PJ, THABET SR, VINH A, WEYAND CM. Inflammation, immunity, and hypertension. Hypertension 57: 132–140, 2011. PubMed PMC

HONETSCHLÄGEROVA Z, HUSKOVÁ Z, VAŇOURKOVÁ Z, SPORKOVÁ A, KRAMER HJ, HWANG SH, TSAI HJ, HAMMOCK BD, IMIG JD, ČERVENKA L, KOPKAN L: Renal mechanisms contributing to the antihypertensive action of soluble epoxide hydrolase inhibition in REN-2 transgenic rats with inducible. J Physiol 589: 207–219, 2011a. PubMed PMC

HONETSCHLÄGEROVÁ Z, SPORKOVÁ A, KOPKAN L, HUSKOVÁ Z, HWANG SH, HAMMOCK BD, IMIG JD, KRAMER HJ, KUJAL P, VERNEROVÁ Z, ČERTÍKOVÁ CHÁBOVÁ V, TESAŘ V, ČERVENKA L: Inhibition of soluble epoxide hydrolase improves the impaired pressure-natriuresis relationship and attenuates the development of hypertension and hypertension-associated end-organ damage in Cyp1a1-Ren-2 transgenic rats. J Hypertens 29: 1590–1601, 2011b. PubMed PMC

HONETSCHLÄGEROVÁ Z, KITADA K, HUSKOVÁ Z, SPORKOVÁ A, KOPKAN L, BÜRGELOVÁ M, VARCABOVÁ A, NISHIYAMA A, HWANG SH, HAMMOCK BD, IMIG JD, KRAMER HJ, KUJAL P, VERNEROVÁ Z, ČERVENKA L: Antihypertensive and renoprotective action of soluble epoxide hydrolase inhibition in ANG II-dependent malignant hypertension are abolished by pretreatment with L-NAME. J Hypertens 31: 321–332, 2013. PubMed PMC

IMIG JD: Epoxides and soluble epoxide hydrolase in cardiovascular physiology. Physiol Rev 92: 101–130, 2012. PubMed PMC

IMIG JD: Epoxyeicosatrienoic acids, hypertension, and kidney injury. Hypertension 65: 476–482, 2015. PubMed PMC

IMIG JD: Prospective for cytochrome P450 epoxygenase cardiovascular and renal therapeutics. Pharmacol Ther 192: 1–19, 2018. PubMed PMC

IMIG JD, HAMMOCK BD: Soluble epoxide hydrolase as a therapeutic target for cardiovascular diseases. Nat Rev Drug Discov 8: 794–805, 2009. PubMed PMC

IMIG JD, RYAN MJ: Immune and inflammatory role in renal disease. Compr Physiol 3: 957–976, 2013. PubMed PMC

IMIG JD, INSCHO EW, DEICHMANN PC, REDDY KM, FALCK JR: Afferent arteriolar vasodilation to the sulfonimide analog of 11, 12-epoxyeicosatrienoic acid involves protein kinase A. Hypertension 33: 408–413, 1999. PubMed

IMIG JD, ZHAO X, CAPDEVILA JH, MORISSEAU C, HAMMOCK BD: Soluble epoxide hydrolase inhibition lowers arterial blood pressure in angiotensin II hypertension. Hypertension 39: 690–694, 2002. PubMed

IMIG JD, DIMITROPOULOU C, REDDY DS, WHITE RE, FALCK JR: Afferent arteriolar dilation to 11,12-EET analogs involves PP2A activity and Ca2+-activated K+ Channels. Microcirculation 15: 137–150, 2008. PubMed PMC

IMIG JD, ELMARAKBY A, NITHIPATIKOM K, WEI S, CAPDEVILA JH, TUNIKI VR, SANGRA B, ANJAIAH S, MANTHATI VL, REDDY DS, FALCK JR: Development of epoxyeicosatrienoic acid analogs with in vivo anti-hypertensive actions. Front Physiol 1: 157, 2010. PubMed PMC

IMIG JD, KHAN MAH, EL-MEANAWY A: Molecular pathways in hypertensive damage In: Disorders of Blood Pressure Regulation: Phenotypes, Mechanisms, Therapeutic Options, BERBARI AE, MANCIA G (eds), Springer, Berlin, 2018, pp 445–463.

JÍCHOVÁ Š, KOPKAN L, HUSKOVÁ Z, DOLEŽELOVÁ S, NECKÁŘ J, KUJAL P, VERNEROVA Z, KRAMER HJ, SADOWSKI J, KOMPANOOWSKA-JEZIERSKA E, REDDY NR, FALCK JR, IMIG JD, ČERVENKA L: Epoxyeicosatrienoic analog attenuates development of malignant hypertension, but does not reverse it once established: a study in Cyp1a1-Ren-2 transgenic rats. J Hypertens 34: 2008–2025, 2016. PubMed PMC

KAERGEL E, MULLER DN, HONECK H, THEUER J, SHAGDARSUREN E, MULLALLY A, LUFT FC, SCHUNCK WH:. P450-dependent arachidonic acid metabolism and angiotensin II-induced renal damage. Hypertension 40: 273–279, 2002. PubMed

KAPLAN NM: Treatment of hypertension: drug therapy In: Clinical Hypertension, KAPLAN NM, FLYNN JT (eds), Lippincott Williams and Wilkins, Philadelphia, 2016, pp 217–230.

KHAN MAH, MANTHATI V, ERRABELLI R, PAVLOV TS, STARUSCHENKO A, FALCK JR, IMIG JD: An orally active epoxyeicosatrienoic acid analog attenuates kidney injury in hypertensive Dahl salt sensitive rat. Hypertension 62: 905–913, 2013. PubMed PMC

KHAN MAH, PAVLOV TS, CHRISTIAN SV, NECKÁŘ J, STARUSCHENKO A, GAUTHIER KM, CAPDEVILA JH, FALCK JR, CAMPBELL WB, IMIG JD: Epoxyeicosatrienoic acid (EET) analog lowers blood pressure through vasodilation and sodium channel inhibition. Clin Sci(Lond) 127: 463–474, 2014. PubMed PMC

KHAN MAH, STAVNIICHUK A, FALCK JR, MOHAMMAD AS, IMIG JD: Epoxyeicosatrienoic acid analog EET-A attenuates lupus nephritis in mice. Front Pharmacol 10: 512, 2019. PubMed PMC

KING LM, GAINER JV, DAVID GL, DAI D, GOLDSTEIN JA, BROWN NJ, ZELDIN DC: Single nucleotide polymorphisms in the CYP2J2 and CYP2C8 genes and the risk of hypertension. Pharmacogenet Genomics 15: 7–13, 2005. PubMed

KUJAL P, ČERTÍKOVÁ CHABOVÁ V, ŠKAROUPKOVÁ P, HUSKOVÁ Z, VERNEROVÁ Z, KRAMER HJ, WALKOWSKA A, KOMPANOWSKA-JEZIERSKA E, SADOWSKI J, KITADA K, NISHIYAMA A, HWANG SH, HAMMOCK BD, IMIG JD, ČERVENKA L: Inhibition of soluble epoxide hydrolase is renoprotective in 5/6 nephrectomized Ren-2 transgenic hypertensive rats. Clin Exp Pharmacol Physiol 41: 227–237, 2014. PubMed PMC

LEE CR, IMIG JD, EDIN ML, FOLEY J, DEGRAFF LM, BRADBURY JA, GRAVES JP, LIH FB, CLARK J, MYERS P, PERROW AL, LEPP AN, KANNON MA, RONNEKLEIV OK, ALKAYED NJ, FALCK JR, TOMER KB, ZELDIN DC: Endothelial expression of human cytochrome P450 epoxygenases lowers blood pressure and attenuates hypertension-induced renal injury in mice. FASEB J 24: 3770–3781, 2010. PubMed PMC

LEE CR, PRETORIUS M, SCHUCK RN, BURCH LH, BARTLETT J, WILLIAMS SM, ZELDIN DC, BROWN NJ: Genetic variation in soluble epoxide hydrolase (EPHX2) is associated with forearm vasodilator responses in humans. Hypertension 57: 116–122, 2011. PubMed PMC

MAKITA K, TAKAHASHI K, KARARA A, JACOBSON HR, FALCK JR, CAPDEVILA JH: Experimental and/or genetically controlled alterations of the renal microsomal cytochrome P450 epoxygenase induce hypertension in rats fed a high salt diet. J Clin Invest 94: 2414–2420, 1994. PubMed PMC

MANHIANI M, QUIGLEY JE, KNIGHT SF, TASOOBSHIRAZI S, MOORE T, BRANDS MW, HAMMOCK BD, IMIG JD: Soluble epoxide hydrolase gene deletion attenuates renal injury and inflammation with DOCA-salt hypertension. Am J Physiol Renal Physiol 297: F740–F448, 2009. PubMed PMC

MARINO JP JR: Soluble epoxide hydrolase, a target with multiple opportunities for cardiovascular drug discovery. Curr Top Med Chem 9: 452–463, 2009. PubMed

MILLS KT, BUNDY JD, KELLY TN, REED JE, KEARNEY PM, REYNOLDS K, CHEN J, HE J. Global disparities of hypertension prevalence and control: a systematic analysis of population-based studies from 90 countries. Circulation 134: 441–450, 2016. PubMed PMC

MONTEZANO AC, TOUYZ RM: Oxidative stress, Noxs, and hypertension: experimental evidence and clinical controversies. Ann Med 44 (Suppl 1): S2–S16, 2012. PubMed

MUNTNER P, DAVIS BR, CUSHMAN WC, BANGALORE S, CALHOUN DA, PRESSEL SL, BLACK HR, KOSTIS JB, PROBSTFIELD JL, WHELTON PK, RAHMAN M, ALLHAT COLLABORATIVE RESEARCH GROUP: Treatment-resistant hypertension and the incidence of cardiovascular disease and end-stage renal disease: results from the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). Hypertension 64: 1012–1021, 2014. PubMed

NECKÁŘ J, HSU A, HYE KHAN MA, GROSS GJ, NITHIPATIKOM K, CYPROVÁ M, BENÁK D, HLAVÁČKOVÁ M, SOTÁKOVÁ-KAŠPAROVÁ D, FALCK JR, SEDMERA D, KOLÁŘ F, IMIG JD: Infarct size-limiting effect of epoxyeicosatrienoic acid analog EET-B is mediated by hypoxia inducible factor-1α via down regulation of prolyl hydroxylase 3. Am J Physiol Heart Circ Physiol 315: H1148–H1158, 2018. PubMed PMC

NODE K, HUO Y, RUAN X, YANG B, SPIECKER M, LEY K, ZELDIN DC, LIAO JK: Anti-inflammatory properties of cytochrome P450 epoxygenase-derived eicosanoids. Science 285: 1276–1279, 1999. PubMed PMC

OLEARCZYK JJ, QUIGLEY JE, MITCHELL B, YAMAMOTO T, KIM IH, NEWMAN JW, LAURIA A, HAMMOCK BD, IMIG JD: Inhibition of the soluble epoxide hydrolase protects the kidney from damage in hypertensive Goto-Kakizaki rats. Clin Sci (Lond) 116: 61–70, 2009. PubMed PMC

POLONIKOV AV, IVANOV VP, SOLODILOVA MA, KHOROSHAYA IV, KOZHUHOV MA, IVAKIN VE, KATARGINA LN, KOLESNIKOVA OE: A common polymorphism G-50T in cytochrome P450 2J2 gene is associated with increased risk of essential hypertension in a Russian population. Dis Markers 24: 119–126, 2008. PubMed PMC

RUDEMILLER N, LUND H, JACOB HJ, GEURTS AM, MATTSON DL, PHYSGEN KNOCKOUT PROGRAM: CD247 modulates blood pressure by altering T-lymphocyte infiltration in the kidney. Hypertension 63: 559–564, 2014. PubMed PMC

SHUEY MM, BILLINGS FT 4TH, WEI S, MILNE GL, NIAN H, YU C, BROWN NJ: Association of gain-of-function EPHX2 polymorphism Lys55Arg with acute kidney injury following cardiac surgery. PLoS One 12: e0175292, 2017. PubMed PMC

SPORKOVÁ A, JÍCHOVÁ S, HUSKOVÁ Z, KOPKAN L, NISHIYAMA A, HWANG SH, HAMMOCK BD, IMIG JD, KOMPANOWSKA-JEZIERSKA E, SADOWSKI J, KRAMER HJ, ČERVENKA L: Different mechanisms of acute versus long-term antihypertensive effects of soluble epoxide hydrolase inhibition: studies in Cyp1a1-Ren-2 transgenic rats. Clin Exp Pharmacol Physiol 41: 1003–1013, 2014. PubMed PMC

SUDHAHAR V, SHAW S, IMIG JD: Epoxyeicosatrienoic acid analogs and vascular function. Curr Med Chem 17: 1181–1190, 2010. PubMed PMC

SUN P, LIN DH, YUE P, JIANG H, GOTLINGER KH, SCHWARTZMAN ML, FALCK JR, GOLI M, WANG WH: High potassium intake enhances the inhibitory effect of 11,12-EET on ENaC. J Am Soc Nephrol 21: 1667–1677, 2010. PubMed PMC

VARCABOVÁ S, HUSKOVÁ Z, KRAMER HJ, HWANG SH, HAMMOCK BD, IMIG JD, KITADA K, ČERVENKA L: Antihypertensive action of soluble epoxide hydrolase inhibition in Ren-2 transgenic rats is mediated by suppression of the intrarenal renin-angiotensin system. Clin Exp Pharmacol Physiol 40: 273–281, 2013. PubMed PMC

VIEL EC, LEMARIE CA, BENKIRANE K, PARADIS P, SCHIFFRIN EL: Immune regulation and vascular inflammation in genetic hypertension. Am J Physiol Heart Circ Physiol 298: H938–H944, 2010. PubMed

YANG L, CHERIYAN J, GUTTERMAN DD, MAYER RJ, AMENT Z, GRIFFIN JL, LAZAAR AL, NEWBY DE, TAL-SINGER R, WILKINSON IB: Mechanisms of vascular dysfunction in COPD and effects of a novel soluble epoxide hydrolase inhibitor in smokers. Chest 151: 555–563, 2017. PubMed PMC

YU BN, LUO CH, WANG D, WANG A, LI Z, ZHANG W, MO W, ZHOU HH: CYP2C9 allele variants in Chinese hypertension patients and healthy controls. Clin Chim Acta 348: 57–61, 2004. PubMed

YU Z, XU F, HUSE LM, MORISSEAU C, DRAPER AJ, NEWMAN JW, PARKER C, GRAHAM L, ENGLER MM, HAMMOCK BD, ZELDIN DC, KROETZ DL: Soluble epoxide hydrolase regulates hydrolysis of vasoactive epoxyeicosatrienoic acids. Circ Res 87: 992–998, 2000. PubMed

ZHANG J, PATEL MB, GRIFFITHS R, MAO A, SONG YS, KARLOVICH NS, SPARKS MA, JIN H, WU M, LIN EE, CROWLEY SD: Tumor necrosis factor-α produced in the kidney contributes to angiotensin II-dependent hypertension. Hypertension 64: 1275–1281, 2014. PubMed PMC

ZHAO X, POLLOCK DM, INSCHO EW, ZELDIN D, IMIG JD: Decreased renal cytochrome P450 2C enzymes and impaired vasodilation are associated with salt-sensitive hypertension. Hypertension 41: 709–714, 2003. PubMed

ZHAO X, YAMAMOTO T, NEWMAN JW, KIM IH, WATANABE T, HAMMOCK BD, STEWART J, POLLOCK JS, POLLOCK DM, IMIG JD: Soluble epoxide hydrolase inhibition protects the kidney from hypertension-induced damage. J Am Soc Nephrol 15: 1244–1253, 2004. PubMed

ZHAO X, DEY A, ROMANKO O, STEPP DW, WANG MH, JIN L, POLLOCK JS, WEBB RC, IMIG JD: Decreased epoxygenase and increased epoxide hydrolase expression in the mesenteric artery of obese Zucker rats. Am J Physiol Regul Integr Comp Physiol 288: R188–R196, 2005. PubMed

Effects of Epoxyeicosatrienoic Acid-Enhancing Therapy on the Course of Congestive Heart Failure in Angiotensin II-Dependent Rat Hypertension: From mRNA Analysis towards Functional In Vivo Evaluation

Kidney Response to Chemotherapy-Induced Heart Failure: mRNA Analysis in Normotensive and Ren-2 Transgenic Hypertensive Rats

Early Renal Vasodilator and Hypotensive Action of Epoxyeicosatrienoic Acid Analog (EET-A) and 20-HETE Receptor Blocker (AAA) in Spontaneously Hypertensive Rats

Epoxyeicosatrienoic Acid Analog and 20-HETE Antagonist Combination Prevent Hypertension Development in Spontaneously Hypertensive Rats