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Journal of Basic and Clinical Physiology and Pharmacology

Editor-in-Chief: Horowitz, Michal

Editorial Board Member: Das, Kusal K. / Epstein, Yoram / S. Gershon MD, Elliot / Haim, Abraham / Kodesh , Einat / Kohen, Ron / Lichtstein, David / Maloyan, Alina / Mechoulam, Raphael / Roth, Joachim / Schneider, Suzanne / Shohami, Esther / Sohmer, Haim / Yoshikawa, Toshikazu

6 Issues per year


CiteScore 2016: 1.01

SCImago Journal Rank (SJR) 2016: 0.349
Source Normalized Impact per Paper (SNIP) 2016: 0.495

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2191-0286
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Volume 25, Issue 1 (Feb 2014)

Issues

Methylglyoxal causes endothelial dysfunction: the role of endothelial nitric oxide synthase and AMP-activated protein kinase α

Saadet Turkseven / Elif Ertuna / Gunay Yetik-Anacak / Mukadder Yasa
Published Online: 2013-10-14 | DOI: https://doi.org/10.1515/jbcpp-2013-0095

Abstract

Background: Methylglyoxal is a major precursor in the formation of advanced glycation end products and is associated with the pathogenesis of diabetes-related vascular complications. The aim of this study was to evaluate whether methylglyoxal induces endothelial dysfunction and to determine the contributors involved in this process.

Methods: Rat thoracic aortic rings were treated for 24 h with 100 μM methylglyoxal by using an organ culture method. A cumulative dose-response curve to acetylcholine was obtained to determine endothelium-dependent relaxation. The protein levels of endothelial nitric oxide synthase (eNOS) and its phosphorylated form at the serine 1177 site [p-eNOS (Ser1177)], heat shock protein 90 (Hsp90), AMP-activated protein kinase α (AMPKα) and its phosphorylated form at the threonine 172 site [p-AMPKα (Thr172)] were evaluated. Superoxide production was determined by lucigenin-chemiluminescence.

Results: Treatment with 100 μM methylglyoxal for 24 h decreased acetylcholine-induced vascular relaxation. The levels of eNOS and p-eNOS (Ser1177) were reduced while no effect on Hsp90 was observed. Levels of p-AMPKα (Thr172) were significantly decreased without any change in total AMPKα protein levels. Superoxide level was not affected by methylglyoxal treatment.

Conclusions: In rat aortic rings, methylglyoxal determines a reduction in endothelium-dependent relaxation. This effect seems to be mediated via a reduction in p-eNOS (Ser1177) and p-AMPKα (Thr172).

Keywords: AMP-activated protein kinase α (AMPKα); endothelium-dependent relaxation; eNOS; methylglyoxal

References

  • 1.

    Gibbons GW, Shaw PM. Diabetic vascular disease: characteristics of vascular disease unique to the diabetic patient. Semin Vasc Surg 2012;25:89–92.Web of SciencePubMedCrossrefGoogle Scholar

  • 2.

    Mudau M, Genis A, Lochner A, Strijdom H. Endothelial dysfunction: the early predictor of atherosclerosis. Cardiovasc J Afr 2012;23:222–31.PubMedCrossrefGoogle Scholar

  • 3.

    Tousoulis D, Briasoulis A, Papageorgiou N, Tsioufis C, Tsiamis E, Toutouzas K, et al. Oxidative stress and endothelial function: therapeutic interventions. Recent Pat Cardiovasc Drug Discov 2011;6:103–14.PubMedGoogle Scholar

  • 4.

    Stern DM, Yan SD, Yan SF, Schmidt AM. Receptor for advanced glycation endproducts (RAGE) and the complications of diabetes. Ageing Res Rev 2002;1:1–15.PubMedCrossrefGoogle Scholar

  • 5.

    Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001;414:813–20.Google Scholar

  • 6.

    Desai K, Wu L. Methylglyoxal and advanced glycation endproducts: new therapeutic horizons? Recent Pat Cardiovasc Drug Discov 2007;2:89–99.PubMedGoogle Scholar

  • 7.

    Wu L. The pro-oxidant role of methylglyoxal in mesenteric artery smooth muscle cells. Can J Physiol Pharmacol 2005;83:63–8.PubMedCrossrefGoogle Scholar

  • 8.

    Kalapos MP. Methylglyoxal in living organisms: chemistry, biochemistry, toxicology and biological implications. Toxicol Lett 1999;110:145–75.CrossrefPubMedGoogle Scholar

  • 9.

    Degenhardt TP, Thorpe SR, Baynes JW. Chemical modification of proteins by methylglyoxal. Cell Mol Biol (Noisy-le-grand) 1998;44:1139–45.Google Scholar

  • 10.

    Wang H, Meng QH, Gordon JR, Khandwala H, Wu L. Proinflammatory and proapoptotic effects of methylglyoxal on neutrophils from patients with type 2 diabetes mellitus. Clin Biochem 2007;40:1232–9.Web of SciencePubMedCrossrefGoogle Scholar

  • 11.

    Wang X, Desai K, Chang T, Wu L. Vascular methylglyoxal metabolism and the development of hypertension. J Hypertens 2005;23:1565–73.CrossrefPubMedGoogle Scholar

  • 12.

    Wang X, Desai K, Clausen JT, Wu L. Increased methylglyoxal and advanced glycation end products in kidney from spontaneously hypertensive rats. Kidney Int 2004;66:2315–21.PubMedCrossrefGoogle Scholar

  • 13.

    Chen ZP, Mitchelhill KI, Michell BJ, Stapleton D, Rodriguez-Crespo I, Witters LA, et al. AMP-activated protein kinase phosphorylation of endothelial NO synthase. FEBS Lett 1999;443:285–9.Google Scholar

  • 14.

    Nagata D, Hirata Y. The role of AMP-activated protein kinase in the cardiovascular system. Hypertens Res 2010;33:22–8.CrossrefPubMedGoogle Scholar

  • 15.

    Garcia-Cardena G, Fan R, Shah V, Sorrentino R, Cirino G, Papapetropoulos A, et al. Dynamic activation of endothelial nitric oxide synthase by Hsp90. Nature 1998;392:821–4.Google Scholar

  • 16.

    Mingone CJ, Ahmad M, Gupte SA, Chow JL, Wolin MS. Heme oxygenase-1 induction depletes heme and attenuates pulmonary artery relaxation and guanylate cyclase activation by nitric oxide. Am J Physiol Heart Circ Physiol 2008;294:H1244–50.Web of ScienceGoogle Scholar

  • 17.

    Yasa M, Kerry Z, Reel B, Yetik AG, Ertuna E, Ozer A. The effects of calcium channel blockers are not related to their chemical structure in the collar model of the rabbit. J Int Med Res 2007;35:59–71.PubMedCrossrefGoogle Scholar

  • 18.

    Abraham NG, Kushida T, McClung J, Weiss M, Quan S, Lafaro R, et al. Heme oxygenase-1 attenuates glucose-mediated cell growth arrest and apoptosis in human microvessel endothelial cells. Circ Res 2003;93:507–14.PubMedGoogle Scholar

  • 19.

    Christ M, Bauersachs J, Liebetrau C, Heck M, Gunther A, Wehling M. Glucose increases endothelial-dependent superoxide formation in coronary arteries by NAD(P)H oxidase activation: attenuation by the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin. Diabetes 2002;51:2648–52.PubMedCrossrefGoogle Scholar

  • 20.

    Garcia-Cardena G, Martasek P, Masters BS, Skidd PM, Couet J, Li S, et al. Dissecting the interaction between nitric oxide synthase (NOS) and caveolin. Functional significance of the nos caveolin binding domain in vivo. J Biol Chem 1997;272:25437–40.Google Scholar

  • 21.

    Zou MH, Wu Y. AMP-activated protein kinase activation as a strategy for protecting vascular endothelial function. Clin Exp Pharmacol Physiol 2008;35:535–45.PubMedCrossrefGoogle Scholar

  • 22.

    de CJ, Wu R, Girouard H, Karas M, EL MA, Laplante MA, et al. Oxidative stress in hypertension. Clin Exp Hypertens 2004;26:593–601.Google Scholar

  • 23.

    Baynes JW, Thorpe SR. Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes 1999;48:1–9.CrossrefPubMedGoogle Scholar

  • 24.

    Kalapos MP. The tandem of free radicals and methylglyoxal. Chem Biol Interact 2008;171:251–71.Web of ScienceGoogle Scholar

  • 25.

    Mukohda M, Morita T, Okada M, Hara Y, Yamawaki H. Long-term methylglyoxal treatment causes endothelial dysfunction of rat isolated mesenteric artery. J Vet Med Sci 2013;75:151–7.PubMedCrossrefGoogle Scholar

  • 26.

    Dhar I, Dhar A, Wu L, Desai K. Arginine attenuates methylglyoxal- and high glucose-induced endothelial dysfunction and oxidative stress by an endothelial nitric-oxide synthase-independent mechanism. J Pharmacol Exp Ther 2012;342:196–204.Web of ScienceGoogle Scholar

  • 27.

    Sena CM, Matafome P, Crisóstomo J, Rodrigues L, Fernandes R, Pereira P, et al. Methylglyoxal promotes oxidative stress and endothelial dysfunction. Pharmacol Res 2012;65:497–506.CrossrefPubMedGoogle Scholar

  • 28.

    Mukohda M, Yamawaki H, Okada M, Hara Y. Methylglyoxal enhances sodium nitroprusside-induced relaxation in rat aorta. J Pharmacol Sci 2010;112:176–83.Web of SciencePubMedCrossrefGoogle Scholar

  • 29.

    Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature 1999;399:601–5.Google Scholar

  • 30.

    Fleming I, Fisslthaler B, Dimmeler S, Kemp BE, Busse R. Phosphorylation of Thr(495) regulates Ca(2+)/calmodulin-dependent endothelial nitric oxide synthase activity. Circ Res 2001;88:E68–75.Google Scholar

  • 31.

    Dhar A, Dhar I, Desai KM, Wu L. Methylglyoxal scavengers attenuate endothelial dysfunction induced by methylglyoxal and high concentrations of glucose. Br J Pharmacol 2010;161:1843–56.Web of ScienceGoogle Scholar

  • 32.

    Brouwers O, Teerlink T, van BJ, Barto R, Stehouwer CD, Schalkwijk CG. Methylglyoxal and methylglyoxal-arginine adducts do not directly inhibit endothelial nitric oxide synthase. Ann N Y Acad Sci 2008;1126:231–4.Google Scholar

  • 33.

    Bento CF, Marques F, Fernandes R, Pereira P. Methylglyoxal alters the function and stability of critical components of the protein quality control. PLoS One 2010;5:e13007.CrossrefWeb of ScienceGoogle Scholar

  • 34.

    Schulz E, Anter E, Zou MH, Keaney JF Jr. Estradiol-mediated endothelial nitric oxide synthase association with heat shock protein 90 requires adenosine monophosphate-dependent protein kinase. Circulation 2005;111:3473–80.PubMedCrossrefGoogle Scholar

  • 35.

    Wu Y, Zhang C, Dong Y, Wang S, Song P, Viollet B, et al. Activation of the AMP-activated protein kinase by eicosapentaenoic acid (EPA, 20:5 n-3) improves endothelial function in vivo. PLoS One 2012;7:e35508.CrossrefGoogle Scholar

  • 36.

    Nagata D, Kiyosue A, Takahashi M, Satonaka H, Tanaka K, Sata M, et al. A new constitutively active mutant of AMP-activated protein kinase inhibits anoxia-induced apoptosis of vascular endothelial cell. Hypertens Res 2009;32:133–9.CrossrefPubMedGoogle Scholar

  • 37.

    Chang T, Wu L. Methylglyoxal, oxidative stress, and hypertension. Can J Physiol Pharmacol 2006;84:1229–38.PubMedCrossrefGoogle Scholar

  • 38.

    Kim J, Son JW, Lee JA, Oh YS, Shinn SH. Methylglyoxal induces apoptosis mediated by reactive oxygen species in bovine retinal pericytes. J Korean Med Sci 2004;19:95–100.CrossrefPubMedGoogle Scholar

  • 39.

    Wu L, Juurlink BH. The impaired glutathione system and its up-regulation by sulforaphane in vascular smooth muscle cells from spontaneously hypertensive rats. J Hypertens 2001;19:1819–25.PubMedCrossrefGoogle Scholar

  • 40.

    Ward RA, McLeish KR. Methylglyoxal: a stimulus to neutrophil oxygen radical production in chronic renal failure? Nephrol Dial Transplant 2004;19:1702–7.PubMedGoogle Scholar

About the article

Corresponding author: Saadet Turkseven, Faculty of Pharmacy, Department of Pharmacology, Ege University, 35100 Bornova-Izmir, Turkey, Phone: +90 2323885266, Fax: +90 2323884687, E-mail:


Received: 2013-07-26

Accepted: 2013-09-12

Published Online: 2013-10-14

Published in Print: 2014-02-01


Citation Information: Journal of Basic and Clinical Physiology and Pharmacology, ISSN (Online) 2191-0286, ISSN (Print) 0792-6855, DOI: https://doi.org/10.1515/jbcpp-2013-0095.

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