Altered bioavailability of epoxyeicosatrienoic acids is associated with conduit artery endothelial dysfunction in type 2 diabetic patients

Thomas Duflot, Lucile Moreau-Grangé, Clothilde Roche, Michèle Iacob, Julien Wils, Isabelle Rémy-Jouet, Anne-Françoise Cailleux, Matthieu Leuillier, Sylvanie Renet, Dongyang Li, Christophe Morisseau, Fabien Lamoureux, Vincent Richard, Gaëtan Prévost, Robinson Joannidès, Jérémy Bellien, Thomas Duflot, Lucile Moreau-Grangé, Clothilde Roche, Michèle Iacob, Julien Wils, Isabelle Rémy-Jouet, Anne-Françoise Cailleux, Matthieu Leuillier, Sylvanie Renet, Dongyang Li, Christophe Morisseau, Fabien Lamoureux, Vincent Richard, Gaëtan Prévost, Robinson Joannidès, Jérémy Bellien

Abstract

Background: This pathophysiological study addressed the hypothesis that soluble epoxide hydrolase (sEH), which metabolizes the vasodilator and anti-inflammatory epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs), contributes to conduit artery endothelial dysfunction in type 2 diabetes.

Methods and results: Radial artery endothelium-dependent flow-mediated dilatation in response to hand skin heating was reduced in essential hypertensive patients (n = 9) and type 2 diabetic subjects with (n = 19) or without hypertension (n = 10) compared to healthy subjects (n = 36), taking into consideration cardiovascular risk factors, flow stimulus and endothelium-independent dilatation to glyceryl trinitrate. Diabetic patients but not non-diabetic hypertensive subjects displayed elevated whole blood reactive oxygen species levels and loss of NO release during heating, assessed by measuring local plasma nitrite variation. Moreover, plasma levels of EET regioisomers increased during heating in healthy subjects, did not change in hypertensive patients and decreased in diabetic patients. Correlation analysis showed in the overall population that the less NO and EETs bioavailability increases during heating, the more flow-mediated dilatation is reduced. The expression and activity of sEH, measured in isolated peripheral blood mononuclear cells, was elevated in diabetic but not hypertensive patients, leading to increased EETs conversion to DHETs. Finally, hyperglycemic and hyperinsulinemic euglycemic clamps induced a decrease in flow-mediated dilatation in healthy subjects and this was associated with an altered EETs release during heating.

Conclusions: These results demonstrate that an increased EETs degradation by sEH and altered NO bioavailability are associated with conduit artery endothelial dysfunction in type 2 diabetic patients independently from their hypertensive status. The hyperinsulinemic and hyperglycemic state in these patients may contribute to these alterations. Trial registration NCT02311075. Registered December 8, 2014.

Keywords: Endothelial dysfunction; Epoxyeicosatrienoic acids; Soluble epoxide hydrolase; Type 2 diabetes.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Presence of conduit artery endothelial dysfunction in type 2 diabetes and essential hypertension. Variations in radial artery diameter (a) and mean wall shear stress (b) in response to hand skin heating, and variation in radial artery diameter in response to glyceryl trinitrate (c) in healthy, hypertensive (HT), type 2 diabetic (T2D) and hypertensive type 2 diabetic (HT + T2D) subjects. Mean values ± SEM are shown. *P < 0.05, **P < 0.01
Fig. 2
Fig. 2
Altered NO bioavailability in type 2 diabetes. Plasma levels of the NO metabolite nitrite (a) before (34 °C) and at the end of hand skin heating (44 °C) in healthy (n = 23), hypertensive (HT; n = 6), type 2 diabetic (T2D; n = 8) and hypertensive type 2 diabetic (HT + T2D; n = 18) subjects. Whole blood levels of reactive oxygen species (ROS) (b) in healthy, hypertensive (HT), type 2 diabetic (T2D) and hypertensive type 2 diabetic (HT + T2D) subjects. Mean values ± SEM are shown. *P < 0.05, **P < 0.01. Linear relationships between the magnitude of radial artery flow-mediated dilatation with the variations in plasma nitrite levels during heating (c) and with ROS levels (d). The dashed lines represent the 95% confidence interval for the regression
Fig. 3
Fig. 3
Type 2 diabetes profoundly impaired EETs bioavailability during endothelial stimulation. Plasma levels of epoxyeicosatrienoic acids (EETs) (a), dihydroxyeicosatrienoic acids (DHETs) (b) regioisomers and total EETs + DHETs levels (c) before (34 °C) and at the end of hand skin heating (44 °C), in healthy (n = 28), hypertensive (HT; n = 8), type 2 diabetic (T2D; n = 9) and hypertensive type 2 diabetic (HT + T2D; n = 19) subjects. Mean values ± SEM are shown. *P < 0.05, **P < 0.01. Linear relationships between the magnitude of radial artery flow-mediated dilatation with the variations in plasma EETs + DHETs during heating (d). The dashed lines represent 95% confidence interval for the regression
Fig. 4
Fig. 4
Increased EETs degradation by sEH in type 2 diabetes. Ratio of plasma 14,15-dihydroxyeicosatrienoic acid-to-14,15-epoxyeicosatrienoic acid (14,15-DHET/14,15-EET) (a), sEH activity (b), mRNA (c) and protein expression (d) in peripheral blood mononuclear cells in healthy, hypertensive (HT), type 2 diabetic (T2D) and hypertensive type 2 diabetic (HT + T2D) subjects. β2M: beta2-microglobulin. Mean values ± SEM are shown. *P < 0.05, **P < 0.01
Fig. 5
Fig. 5
Acute hyperglycemia and hyperinsulinemia altered conduit artery endothelial function in healthy subjects. Variations in radial artery diameter (a) and mean wall shear stress (b) in response to hand skin heating and variation in radial artery diameter in response to glyceryl trinitrate (c) during saline infusion an during the hyperglycemic (HyperGly) and hyperinsulinemic euglycemic (HyperInsu) clamps in 8 healthy subjects. Plasma levels of nitrite (d) and total epoxyeicosatrienoic acids + dihydroxyeicosatrienoic acids (EETs + DHETs) (e) at baseline at 34 °C, at steady-state and at the end of hand skin heating at 44 °C during saline infusion and during the hyperglycemic and hyperinsulinemic euglycemic clamps in 8 healthy subjects. Mean values ± SEM are shown. *P < 0.05, **P < 0.01

References

    1. van Sloten TT, Henry RM, Dekker JM, Nijpels G, Unger T, Schram MT, Stehouwer CD. Endothelial dysfunction plays a key role in increasing cardiovascular risk in type 2 diabetes: the Hoorn study. Hypertension. 2014;64:1299–1305. doi: 10.1161/HYPERTENSIONAHA.114.04221.
    1. Sena CM, Pereira AM, Seiça R. Endothelial dysfunction—a major mediator of diabetic vascular disease. Biochim Biophys Acta. 2013;1832:2216–2231. doi: 10.1016/j.bbadis.2013.08.006.
    1. Roche C, Besnier M, Cassel R, Harouki N, Coquerel D, Guerrot D, Nicol L, Loizon E, Morisseau C, Remy-Jouet I, Mulder P, Ouvrard-Pascaud A, Madec AM, Richard V, Bellien J. Soluble epoxide hydrolase inhibition improves coronary endothelial function and prevents the development of cardiac alterations in obese insulin-resistant mice. Am J Physiol Heart Circ Physiol. 2015;308:H1020–H1029. doi: 10.1152/ajpheart.00465.2014.
    1. Zhao X, Dey A, Romanko OP, Stepp DW, Wang MH, Zhou Y, 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. 2005;288:R188–R196. doi: 10.1152/ajpregu.00018.2004.
    1. Bellien J, Joannides R, Richard V, et al. Modulation of cytochrome-derived epoxyeicosatrienoic acids pathway: a promising pharmacological approach to prevent endothelial dysfunction in cardiovascular diseases? Pharmacol Ther. 2011;131:1–17. doi: 10.1016/j.pharmthera.2011.03.015.
    1. Morisseau C, Hammock BD. Impact of soluble epoxide hydrolase and epoxyeicosanoids on human health. Annu Rev Pharmacol Toxicol. 2013;53:37–58. doi: 10.1146/annurev-pharmtox-011112-140244.
    1. 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 NO and endothelin-1 pathways to conduit artery endothelial dysfunction in essential hypertension. Circulation. 2012;125:1266–1275. doi: 10.1161/CIRCULATIONAHA.111.070680.
    1. Zhang LN, Vincelette J, Chen D, Gless RD, Anandan SK, Rubanyi GM, Webb HK, MacIntyre DE, Wang YX. Inhibition of soluble epoxide hydrolase attenuates endothelial dysfunction in animal models of diabetes, obesity and hypertension. Eur J Pharmacol. 2011;654:68–74. doi: 10.1016/j.ejphar.2010.12.016.
    1. Gangadhariah MH, Dieckmann BW, Lantier L, Kang L, Wasserman DH, Chiusa M, Caskey CF, Dickerson J, Luo P, Gamboa JL, Capdevila JH, Imig JD, Yu C, Pozzi A, Luther JM. Cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids contribute to insulin sensitivity in mice and in humans. Diabetologia. 2017;60:1066–1075. doi: 10.1007/s00125-017-4260-0.
    1. Duflot T, Pereira T, Roche C, Iacob M, Cardinael P, Hamza NE, Thuillez C, Compagnon P, Joannidès R, Lamoureux F, Bellien J. A sensitive LC–MS/MS method for the quantification of regioisomers of epoxyeicosatrienoic and dihydroxyeicosatrienoic acids in human plasma during endothelial stimulation. Anal Bioanal Chem. 2017;409:1845–1855. doi: 10.1007/s00216-016-0129-1.
    1. Bellien J, Iacob M, Monteil C, Rémy-Jouet I, Duflot T, Thuillez C, Richard V, Joannidès R. Physiological role of endothelin-1 in flow-mediated vasodilatation in humans and impact of cardiovascular risk factors. J Hypertens. 2017;35:1204–1212. doi: 10.1097/HJH.0000000000001307.
    1. Li D, Cui Y, Morisseau C, Gee SJ, Bever CS, Liu X, Wu J, Hammock BD, Ying Y. Nanobody based immunoassay for human soluble epoxide hydrolase detection using polymeric horseradish peroxidase (PolyHRP) for signal enhancement: the rediscovery of PolyHRP? Anal Chem. 2017;89:6248–6256. doi: 10.1021/acs.analchem.7b01247.
    1. Borhan B, Mebrahtu T, Nazarian S, Kurth MJ, Hammock BD. Improved radiolabeled substrates for soluble epoxide hydrolase. Anal Biochem. 1995;231:188–200. doi: 10.1006/abio.1995.1520.
    1. Enderle MD, Benda N, Schmuelling RM, Haering HU, Pfohl M. Preserved endothelial function in IDDM patients, but not in NIDDM patients, compared with healthy subjects. Diabetes Care. 1998;21:271–277. doi: 10.2337/diacare.21.2.271.
    1. Meyer MF, Lieps D, Schatz H, Pfohl M. Impaired flow-mediated vasodilation in type 2 diabetes: lack of relation to microvascular dysfunction. Microvasc Res. 2008;76:61–65. doi: 10.1016/j.mvr.2008.03.001.
    1. Naka KK, Papathanassiou K, Bechlioulis A, Kazakos N, Pappas K, Tigas S, Makriyiannis D, Tsatsoulis A, Michalis LK. Determinants of vascular function in patients with type 2 diabetes. Cardiovasc Diabetol. 2012;11:127. doi: 10.1186/1475-2840-11-127.
    1. Modena MG, Bonetti L, Coppi F, Bursi F, Rossi R. Prognostic role of reversible endothelial dysfunction in hypertensive postmenopausal women. J Am Coll Cardiol. 2002;40:505–510. doi: 10.1016/S0735-1097(02)01976-9.
    1. Ghiadoni L, Versari D, Magagna A, Kardasz I, Plantinga Y, Giannarelli C, Taddei S, Salvetti A. Ramipril dose-dependently increases nitric oxide availability in the radial artery of essential hypertension patients. J Hypertens. 2007;25:361–366. doi: 10.1097/HJH.0b013e3280115901.
    1. Cosentino F, Hishikawa K, Katusic ZS, Lüscher TF. High glucose increases nitric oxide synthase expression and superoxide anion generation in human aortic endothelial cells. Circulation. 1997;96(1):25–28. doi: 10.1161/01.CIR.96.1.25.
    1. Adela R, Nethi SK, Bagul PK, Barui AK, Mattapally S, Kuncha M, Patra CR, Reddy PN, Banerjee SK. Hyperglycaemia enhances nitric oxide production in diabetes: a study from South Indian patients. PLoS ONE. 2015;10:e0125270. doi: 10.1371/journal.pone.0125270.
    1. McVeigh GE, Brennan GM, Johnston GD, McDermott BJ, McGrath LT, Henry WR, Andrews JW, Hayes JR. Impaired endothelium-dependent and independent vasodilation in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia. 1992;35:771–776.
    1. Heitzer T, Krohn K, Albers S, Meinertz T. Tetrahydrobiopterin improves endothelium-dependent vasodilation by increasing nitric oxide activity in patients with type II diabetes mellitus. Diabetologia. 2000;43:1435–1458. doi: 10.1007/s001250051551.
    1. Minuz P, Jiang H, Fava C, Turolo L, Tacconelli S, Ricci M, Patrignani P, Morganti A, Lechi A, McGiff JC. Altered release of cytochrome p450 metabolites of arachidonic acid in renovascular disease. Hypertension. 2008;51:1379–1385. doi: 10.1161/HYPERTENSIONAHA.107.105395.
    1. Issan Y, Hochhauser E, Guo A, Gotlinger KH, Kornowski R, Leshem-Lev D, Lev E, Porat E, Snir E, Thompson CI, Abraham NG, Laniado-Schwartzman M. Elevated level of pro-inflammatory eicosanoids and EPC dysfunction in diabetic patients with cardiac ischemia. Prostaglandins Other Lipid Mediat. 2013;100–101:15–21. doi: 10.1016/j.prostaglandins.2012.12.002.
    1. 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. 1994;94:2414–2420. doi: 10.1172/JCI117608.
    1. Wang MH, Smith A, Zhou Y, Chang HH, Lin S, Zhao X, Imig JD, Dorrance AM. Downregulation of renal CYP-derived eicosanoid synthesis in rats with diet-induced hypertension. Hypertension. 2003;42:594–599. doi: 10.1161/.
    1. Furukawa M, Nishimura M, Ogino D, Chiba R, Ikai I, Ueda N, Naito S, Kuribayashi S, Moustafa MA, Uchida T, Sawada H, Kamataki T, Funae Y, Fukumoto M. Cytochrome p450 gene expression levels in peripheral blood mononuclear cells in comparison with the liver. Cancer Sci. 2004;95:520–529. doi: 10.1111/j.1349-7006.2004.tb03243.x.
    1. Huang H, Morisseau C, Wang J, Yang T, Falck JR, Hammock BD, Wang MH. Increasing or stabilizing renal epoxyeicosatrienoic acid production attenuates abnormal renal function and hypertension in obese rats. Am J Physiol Renal Physiol. 2007;293:F342–F349. doi: 10.1152/ajprenal.00004.2007.
    1. De Taeye BM, Morisseau C, Coyle J, Covington JW, Luria A, Yang J, Murphy SB, Friedman DB, Hammock BB, Vaughan DE. Expression and regulation of soluble epoxide hydrolase in adipose tissue. Obesity (Silver Spring) 2010;18:489–498. doi: 10.1038/oby.2009.227.
    1. Liu Y, Dang H, Li D, Pang W, Hammock BD, Zhu Y. Inhibition of soluble epoxide hydrolase attenuates high-fat-diet-induced hepatic steatosis by reduced systemic inflammatory status in mice. PLoS ONE. 2012;7:e39165. doi: 10.1371/journal.pone.0039165.
    1. Ai D, Fu Y, Guo D, Tanaka H, Wang N, Tang C, Hammock BD, Shyy JY, Zhu Y. Angiotensin II up-regulates soluble epoxide hydrolase in vascular endothelium in vitro and in vivo. Proc Natl Acad Sci USA. 2007;104:9018–9023. doi: 10.1073/pnas.0703229104.
    1. Poreba M, Rostoff P, Siniarski A, Mostowik M, Golebiowska-Wiatrak R, Nessler J, Undas A, Gajos G. Relationship between polyunsaturated fatty acid composition in serum phospholipids, systemic low-grade inflammation, and glycemic control in patients with type 2 diabetes and atherosclerotic cardiovascular disease. Cardiovasc Diabetol. 2018;17:29. doi: 10.1186/s12933-018-0672-5.
    1. Poreba M, Mostowik M, Siniarski A, Golebiowska-Wiatrak R, Malinowski KP, Haberka M, Konduracka E, Nessler J, Undas A, Gajos G. Treatment with high-dose n-3 PUFAs has no effect on platelet function, coagulation, metabolic status or inflammation in patients with atherosclerosis and type 2 diabetes. Cardiovasc Diabetol. 2017;16:50. doi: 10.1186/s12933-017-0523-9.
    1. Ward NC, Rivera J, Hodgson J, Puddey IB, Beilin LJ, Falck JR, Croft KD. Urinary 20-hydroxyeicosatetraenoic acid is associated with endothelial dysfunction in humans. Circulation. 2004;110:438–443. doi: 10.1161/01.CIR.0000136808.72912.D9.
    1. Steinberg HO, Brechtel G, Johnson A, Fineberg N, Baron AD. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. A novel action of insulin to increase nitric oxide release. J Clin Invest. 1994;94:1172–1179. doi: 10.1172/JCI117433.
    1. Baron AD, Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G. Insulin-mediated skeletal muscle vasodilation contributes to both insulin sensitivity and responsiveness in lean humans. J Clin Invest. 1995;96:786–792. doi: 10.1172/JCI118124.
    1. Hou HH, Hammock BD, Su KH, Morisseau C, Kou YR, Imaoka S, Oguro A, Shyue SK, Zhao JF, Lee TS. N-terminal domain of soluble epoxide hydrolase negatively regulates the VEGF-mediated activation of endothelial nitric oxide synthase. Cardiovasc Res. 2012;93:120–129. doi: 10.1093/cvr/cvr267.
    1. Hou HH, Liao YJ, Hsiao SH, Shyue SK, Lee TS. Role of phosphatase activity of soluble epoxide hydrolase in regulating simvastatin-activated endothelial nitric oxide synthase. Sci Rep. 2015;5:13524. doi: 10.1038/srep13524.
    1. Williams SB, Goldfine AB, Timimi FK, Ting HH, Roddy MA, Simonson DC, Creager MA. Acute hyperglycemia attenuates endothelium-dependent vasodilation in humans in vivo. Circulation. 1998;97:1695–1701. doi: 10.1161/01.CIR.97.17.1695.
    1. Kawano H, Motoyama T, Hirashima O, Hirai N, Miyao Y, Sakamoto T, Kugiyama K, Ogawa H, Yasue H. Hyperglycemia rapidly suppresses flow-mediated endothelium-dependent vasodilation of brachial artery. J Am Coll Cardiol. 1999;34:146–154. doi: 10.1016/S0735-1097(99)00168-0.
    1. Title LM, Cummings PM, Giddens K, Nassar BA. Oral glucose loading acutely attenuates endothelium-dependent vasodilation in healthy adults without diabetes: an effect prevented by vitamins C and E. J Am Coll Cardiol. 2000;36:2185–2191. doi: 10.1016/S0735-1097(00)00980-3.
    1. Beckman JA, Goldfine AB, Gordon MB, Creager MA. Ascorbate restores endothelium-dependent vasodilation impaired by acute hyperglycemia in humans. Circulation. 2001;103:1618–1623. doi: 10.1161/01.CIR.103.12.1618.
    1. Arcaro G, Cretti A, Balzano S, Lechi A, Muggeo M, Bonora E, Bonadonna RC. Insulin causes endothelial dysfunction in humans: sites and mechanisms. Circulation. 2002;105:576–582. doi: 10.1161/hc0502.103333.
    1. Campia U, Sullivan G, Bryant MB, Waclawiw MA, Quon MJ, Panza JA. Insulin impairs endothelium-dependent vasodilation independent of insulin sensitivity or lipid profile. Am J Physiol Heart Circ Physiol. 2004;286:H76–H82. doi: 10.1152/ajpheart.00539.2003.
    1. Weintraub NL, Fang X, Kaduce TL, VanRollins M, Chatterjee P, Spector AA. Potentiation of endothelium-dependent relaxation by epoxyeicosatrienoic acids. Circ Res. 1997;81:258–267. doi: 10.1161/01.RES.81.2.258.
    1. Hu J, Dziumbla S, Lin J, Bibli SI, Zukunft S, de Mos J, Awwad K, Frömel T, Jungmann A, Devraj K, Cheng Z, Wang L, Fauser S, Eberhart CG, Sodhi A, Hammock BD, Liebner S, Müller OJ, Glaubitz C, Hammes HP, Popp R, Fleming I. Inhibition of soluble epoxide hydrolase prevents diabetic retinopathy. Nature. 2017;552:248–252.
    1. Luria A, Bettaieb A, Xi Y, Shieh GJ, Liu HC, Inoue H, Tsai HJ, Imig JD, Haj FG, Hammock BD. Soluble epoxide hydrolase deficiency alters pancreatic islet size and improves glucose homeostasis in a model of insulin resistance. Proc Natl Acad Sci USA. 2011;108:9038–9043. doi: 10.1073/pnas.1103482108.

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