Abstract
Endothelial dysfunction is considered as a major risk factor of cardiovascular complications of type I and types II diabetes. Impaired endothelium-dependent vasodilatation can be directly linked to a decreased synthesis of the endothelium-derived nitric oxide (NO) and/or an increase in the production of reactive oxygen species such as superoxide. Administration of tetrahydrobiopterin, an important co-factor for the enzyme nitric oxide synthase (NOS), has been demonstrated to enhance NO production in prehypertensive rats, restore endothelium-dependent vasodilatation in coronary arteries following reperfusion injury, aortae from streptozotocin-induced diabetic rats and in patients with hypercholesterolemia. Tetrahydrobiopterin supplementation has been shown to improve endothelium-dependent relaxation in normal individuals, patients with type II diabetes and in smokers. These findings from different animal models as well as in clinical trials lead to the hypothesis that tetrahydrobiopterin, or a precursor thereof, could be a new and an effective therapeutic approach for the improvement of endothelium function in pathophysiological conditions. In addition to NO, the endothelium also produces a variety of other vasoactive factors and a key question is: Is there also a link to changes in the synthesis/action of these other endothelium-derived factors to the cardiovascular complications associated with diabetes? Endothelium-derived hyperpolarizing factor, or EDHF, is thought to be an extremely important vasodilator substance notably in the resistance vasculature. Unfortunately, the nature and, indeed, the very existence of EDHF remains obscure. Potentially there are multiple EDHFs demonstrating vessel selectivity in their actions. However, until now, identity and properties of EDHF that determine the therapeutic potential of manipulating EDHF remains unknown. Here we briefly review the current status of EDHF and the link between EDHF and endothelial dysfunction associated with diabetes. (Mol Cell Biochem 263: 21–27, 2004)
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References
Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M: Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 339: 229–234, 1998.
Rubanyi GM: The role of endothelium in cardiovascular homeostasis and diseases. J Cardiovasc Pharmacol 22 (Suppl 4): S1–S14, 1993
De Vriese AS, Verbeuren TJ, Van d, V, Lameire NH, Vanhoutte PM: Endothelial dysfunction in diabetes. Br J Pharmacol 130: 963–974, 2000
Bucala R, Tracey KJ, Cerami A: Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes. J Clin Invest 87: 432–438, 1991
Vlassara H, Fuh H, Makita Z, Krungkrai S, Cerami A, Bucala R: Exogenous advanced glycosylation end products induce complex vascular dysfunction in normal animals: A model for diabetic and aging compli-cations. Proc Natl Acad Sci USA 89: 12043–12047, 1992
Giugliano D, Ceriello A, Paolisso G: Oxidative stress and diabetic vascular complications. Diabetes Care 19: 257–267, 1996
Gabbay KH: The sorbitol pathway and the complications of diabetes. N Engl J Med 288: 831–836, 1973
Williams B, Schrier RW: Glucose-induced protein kinase C activity regulates arachidonic acid release and eicosanoid production by cultured glomerular mesangial cells. J Clin Invest 92: 2889–2896, 1993
Lee TS, Saltsman KA, Ohashi H, King GL: Activation of protein kinase C byelevation of glucose concentration: Proposal for a mechanism in the development of diabetic vascular complications. Proc Natl Acad Sci USA 86: 5141–5145, 1989
Mather K, Anderson TJ, Verma S: Insulin action in the vasculature: Physiology and pathophysiology. J Vasc Res 38: 415–422, 2001
Wolff SP, Dean RT: Glucose autoxidation and protein modification. The potential role of autoxidative glycosylation' in diabetes. Biochem J 245: 243–250, 1987
Tesfamariam B, Cohen RA: Free radicals mediate endothelial cell dys-function caused by elevated glucose. Am J Physiol 263: H321–H326, 1992
Yan SD, Schmidt AM, Anderson GM, Zhang J, Brett J, Zou YS, Pinsky D, Stern D: Enhanced cellular oxidant stress by the interaction of advanced glycation end products with their receptors/binding proteins. J Biol Chem 269: 9889–9897, 1994
Makimattila S, Liu ML, Vakkilainen J, Schlenzka A, Lahdenpera S, Syvanne M, Mantysaari M, Summanen P, Bergholm R, Taskinen MR, Yki-Jarvinen H: Impaired endothelium-dependent vasodilation in type 2 diabetes. Relation to LDL size, oxidized LDL, and antioxidants. Diabetes Care 22: 973–981, 1999
Cai H, Harrison DG: Endothelial dysfunction in cardiovascular diseases: The role of oxidant stress. Circ Res 87: 840–844, 2000
Katusic ZS: Vascular endothelial dysfunction: Does tetrahydrobiopterin play a role? Am J Physiol Heart Circ Physiol 281: H981–H986, 2001
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
Sun J, Sui X, Bradbury JA, Zeldin DC, Conte MS, Liao JK: Inhibition of vascular smooth muscle cell migration by cytochrome p450 epoxygenase-derived eicosanoids. Circ Res 90: 1020–1027, 2002
Yang B, Graham L, Dikalov S, Mason RP, Falck JR, Liao JK, Zeldin DC: Overexpression of cytochrome P450 CYP2J2 protects against hypoxia-reoxygenation injury in cultured bovine aortic endothelial cells. Mol Pharmacol 60: 310–320, 2001
Pomposiello SI, Carroll MA, Falck JR, McGiff JC: Epoxyeicosatrienoic acid-mediated renal vasodilation to arachidonic acid is enhanced in SHR. Hypertension 37: 887–893, 2001
McGuire JJ, Ding H, Triggle CR: Endothelium-derived relaxing factors: Afocus on endothelium-derived hyperpolarizing factor(s). Can J Physiol Pharmacol 79: 443–470, 2001
Bolotina VM, Najibi S, Palacino JJ, Pagano PJ, Cohen RA: Nitric oxide directly activates calcium-dependent potassium channels in vascular smooth muscle. Nature 368: 850–853, 1994
Mistry DK, Garland CJ: Nitric oxide (NO)-induced activation of large conductance Ca2+-dependent K+ channels (BK(Ca)) in smooth muscle cells isolated from the rat mesenteric artery. Br J Pharmacol 124: 1131–1140, 1998
Garland JG, McPherson GA: Evidence that nitric oxide does not mediate the hyperpolarization and relaxation to acetylcholine in the rat small mesenteric artery. Br J Pharmacol 105: 429–435, 1992
Parkington HC, Tonta MA, Coleman HA, Tare M: Role of membrane potential in endothelium-dependent relaxation of guinea-pig coronary arterial smooth muscle. J Physiol 484(2): 469–480, 1995
Murphy ME, Brayden JE: Apamin-sensitive potassium channel medi-ate an endothelium-dependent hyperpolarization in rabbit mesenteric arteries. J Physiol 489(Pt 1): 723–734, 1995.
Dong H, Waldron GJ, Cole WC, Triggle CR: Roles of calcium-activated and voltage-gated delayed rectifier potassium channels in endothelium-dependent vasorelaxation of the rabbit middle cerebral artery. Br J Phar-macol 123: 821–832, 1998
Zakhary R, Gaine SP, Dinerman JL, Ruat M, Flavahan NA, Snyder SH: Heme oxygenase 2: Endothelial and neuronal localization and role in endothelium-dependent relaxation. Proc Natl Acad Sci USA 93: 795–798, 1996
Feletou M, Vanhoutte PM: The third pathway: Endothelium-dependent hyperpolarization. J Physiol Pharmacol 50: 525–534, 1999
Edwards G, Dora KA, Gardener MJ, Garland CJ, Weston AH: K+ is an endothelium-derived hyperpolarizing factor in rat arteries. Nature 396: 269–272, 1998
Campbell WB, Harder DR: Endothelium-derived hyperpolarizing fac-tors and vascular cytochrome P450 metabolites of arachidonic acid in the regulation of tone. Circ Res 84: 484–488, 1999
Fleming I: Cytochrome p450 and vascular homeostasis. Circ Res 89: 753–762, 2001
Janssen LJ: Are endothelium-derived hyperpolarizing and contracting factors isoprostanes? Trends Pharmacol Sci 23: 59–62, 2002
Randall MD, Alexander SP, Bennett T, Boyd EA, Fry JR, Gardiner SM, Kemp PA, McCulloch AI, Kendall DA: An endogenous cannabinoid as an endothelium-derived vasorelaxant. Biochem Biophys Res Commun 229: 114–120, 1996
Pannirselvam M, Verma S, Anderson TJ, Triggle CR: Cellular basis of endothelial dysfunction in small mesenteric arteries from spontaneously diabetic (db/db-/-) mice: role of decreased tetrahydrobiopterin bioavail-ability. Br J Pharmacol 136: 255–263, 2002
Stroes E, Hijmering M, van Zandvoort M, Wever R, Rabelink TJ, van Faassen EE: Origin of superoxide production by endothelial nitric oxide synthase. FEBS Lett 438: 161–164, 1998
Barlow RS, White RE: Hydrogen peroxide relaxes porcine coronary arteries by stimulating BKCa channel activity. Am J Physiol 275: H1283–H1289, 1998
Bychkov R, Pieper K, Ried C, Milosheva M, Bychkov E, Luft FC, Haller H: Hydrogen peroxide, potassium currents, and membrane potential in human endothelial cells. Circulation 99: 1719–1725, 1999
Beny JL, der Weid PY: Hydrogen peroxide: An endogenous smooth muscle cell hyperpolarizing factor. Biochem Biophys Res Commun176: 378–384, 1991
Matoba T, Shimokawa H, Nakashima M, Hirakawa Y, Mukai Y, Hirano K, Kanaide H, Takeshita A: Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in mice. J Clin Invest 106: 1521–1530, 2000
Watkins MT, Patton GM, Soler HM, Albadawi H, Humphries DE, Evans JE, Kadowaki H: Synthesis of 8-epi-prostaglandin F2alpha by human endothelial cells: Role of prostaglandin H2 synthase. Biochem J 344(Pt 3): 747–754, 1999
Ding H, Triggle CR: Novel endothelium-derived relaxing factors. Iden-tification of factors and cellular targets. J Pharmacol Toxicol Methods 44: 441–452, 2000.
Vanhoutte PM: Vascular biology. Old-timer makes a comeback. Nature 396: 213, 215–216, 1998
Kumar NM, Gilula NB: The gap junction communication channel. Cell 84: 381–388, 1996
Christ GJ, Spray DC, el Sabban M, Moore LK, Brink PR: Gap junctions in vascular tissues. Evaluating the role of intercellular communication in the modulation of vasomotor tone. Circ Res 79: 631–646, 1996
van Kempen MJ, Jongsma HJ: Distribution of connexin37, connexin40 and connexin43 in the aorta and coronary artery of several mammals. Histochem Cell Biol 112: 479–486, 1999
Little TL, Beyer EC, Duling BR: Connexin 43 and connexin 40 gap junc-tional proteins are present in arteriolar smooth muscle and endothelium in vivo. Am J Physiol 268: H729–H739, 1995
Brink P: Gap junction voltage dependence. A clear picture emerges. J Gen Physiol 116: 11–12, 2000
Waldron GJ, Ding H, Lovren F, Kubes P, Triggle CR: Acetylcholine-induced relaxation of peripheral arteries isolated from mice lacking endothelial nitric oxide synthase. Br J Pharmacol 128: 653–658, 1999
Ding H, Kubes P, Triggle C: Potassium-and acetylcholine-induced va-sorelaxation in mice lacking endothelial nitric oxide synthase. Br J Pharmacol 129: 1194–1200, 2000
Fujii K, Tominaga M, Ohmori S, Kobayashi K, Koga T, Takata Y, Fujishima M: Decreased endothelium-dependent hyperpolarization to acetylcholine in smooth muscle of the mesenteric artery of spontaneously hypertensive rats. Circ Res 70: 660–669, 1992
Fukao M, Hattori Y, Kanno M, Sakuma I, Kitabatake A: Alterations in endothelium-dependent hyperpolarization and relaxation in mesenteric arteries from streptozotocin-induced diabetic rats. Br J Pharmacol 121: 1383–1391, 1997
Makino A, Ohuchi K, Kamata K: Mechanisms underlying the attenua-tion of endothelium-dependent vasodilatation in the mesenteric arterial bed of the streptozotocin-induced diabetic rat. Br J Pharmacol 130: 549–556, 2000
Wigg SJ, Tare M, Tonta MA, O'Brien RC, Meredith IT, Parkington HC: Comparison of effects of diabetes mellitus on an EDHF-dependent and an EDHF-independent artery. Am J Physiol Heart Circ Physiol 281: H232–H240, 2001
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Triggle, C.R., Ding, H., Anderson, T.J. et al. The endothelium in health and disease: A discussion of the contribution of non-nitric oxide endothelium-derived vasoactive mediators to vascular homeostasis in normal vessels and in type II diabetes. Mol Cell Biochem 263, 21–27 (2004). https://doi.org/10.1023/B:MCBI.0000041845.62061.c9
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DOI: https://doi.org/10.1023/B:MCBI.0000041845.62061.c9