Methylglyoxal causes endothelial dysfunction: the role of endothelial nitric oxide synthase and AMP-activated protein kinase α
-
Saadet Turkseven
,
Elif Ertuna
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).
This study was supported by a Grant of Ege University Fund for Scientific Research (93ECZ028).
Conflict of interest statement
Authors’ conflict of interest disclosure: The authors stated that there are no conflicts of interest regarding the publication of this article. Research funding played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
References
1. Gibbons GW, Shaw PM. Diabetic vascular disease: characteristics of vascular disease unique to the diabetic patient. Semin Vasc Surg 2012;25:89–92.10.1053/j.semvascsurg.2012.04.005Search in Google Scholar
2. Mudau M, Genis A, Lochner A, Strijdom H. Endothelial dysfunction: the early predictor of atherosclerosis. Cardiovasc J Afr 2012;23:222–31.10.5830/CVJA-2011-068Search in Google 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;6:103–14.10.2174/157489011795933819Search in Google 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;1:1–15.10.1016/S0047-6374(01)00366-9Search in Google Scholar
5. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001;414:813–20.10.1038/414813aSearch in Google Scholar
6. Desai K, Wu L. Methylglyoxal and advanced glycation endproducts: new therapeutic horizons? Recent Pat Cardiovasc Drug Discov 2007;2:89–99.10.2174/157489007780832498Search in Google Scholar
7. Wu L. The pro-oxidant role of methylglyoxal in mesenteric artery smooth muscle cells. Can J Physiol Pharmacol 2005;83:63–8.10.1139/y04-112Search in Google Scholar
8. Kalapos MP. Methylglyoxal in living organisms: chemistry, biochemistry, toxicology and biological implications. Toxicol Lett 1999;110:145–75.10.1016/S0378-4274(99)00160-5Search in Google Scholar
9. Degenhardt TP, Thorpe SR, Baynes JW. Chemical modification of proteins by methylglyoxal. Cell Mol Biol (Noisy-le-grand) 1998;44:1139–45.Search in 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;40:1232–9.10.1016/j.clinbiochem.2007.07.016Search in Google Scholar PubMed
11. Wang X, Desai K, Chang T, Wu L. Vascular methylglyoxal metabolism and the development of hypertension. J Hypertens 2005;23:1565–73.10.1097/01.hjh.0000173778.85233.1bSearch in Google Scholar PubMed
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;66:2315–21.10.1111/j.1523-1755.2004.66034.xSearch in Google 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;443:285–9.10.1016/S0014-5793(98)01705-0Search in Google Scholar
14. Nagata D, Hirata Y. The role of AMP-activated protein kinase in the cardiovascular system. Hypertens Res 2010;33:22–8.10.1038/hr.2009.187Search in Google Scholar PubMed
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;392:821–4.10.1038/33934Search in Google Scholar PubMed
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:H1244–50.10.1152/ajpheart.00846.2007Search in Google Scholar PubMed PubMed Central
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;35:59–71.10.1177/147323000703500106Search in Google Scholar PubMed
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;93:507–14.10.1161/01.RES.0000091828.36599.34Search in Google Scholar PubMed
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;51:2648–52.10.2337/diabetes.51.8.2648Search in Google Scholar PubMed
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.Search in 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;35:535–45.10.1111/j.1440-1681.2007.04851.xSearch in Google Scholar PubMed PubMed Central
22. de CJ, Wu R, Girouard H, Karas M, EL MA, Laplante MA, et al. Oxidative stress in hypertension. Clin Exp Hypertens 2004;26:593–601.10.1081/CEH-200031904Search in Google Scholar
23. Baynes JW, Thorpe SR. Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes 1999;48:1–9.10.2337/diabetes.48.1.1Search in Google Scholar PubMed
24. Kalapos MP. The tandem of free radicals and methylglyoxal. Chem Biol Interact 2008;171:251–71.10.1016/j.cbi.2007.11.009Search in Google Scholar PubMed
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;75:151–7.10.1292/jvms.12-0345Search in Google Scholar PubMed
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;342:196–204.10.1124/jpet.112.192112Search in Google Scholar PubMed
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;65:497–506.10.1016/j.phrs.2012.03.004Search in Google Scholar PubMed
28. Mukohda M, Yamawaki H, Okada M, Hara Y. Methylglyoxal enhances sodium nitroprusside-induced relaxation in rat aorta. J Pharmacol Sci 2010;112:176–83.10.1254/jphs.09219FPSearch in Google Scholar PubMed
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;399:601–5.10.1038/21224Search in Google Scholar PubMed
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:E68–75.10.1161/hh1101.092677Search in Google Scholar PubMed
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;161:1843–56.10.1111/j.1476-5381.2010.01017.xSearch in Google Scholar PubMed PubMed Central
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;1126:231–4.10.1196/annals.1433.017Search in Google Scholar PubMed
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:e13007.10.1371/journal.pone.0013007Search in Google Scholar PubMed PubMed Central
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;111:3473–80.10.1161/CIRCULATIONAHA.105.546812Search in Google Scholar PubMed
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:e35508.10.1371/journal.pone.0035508Search in Google Scholar PubMed PubMed Central
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;32:133–9.10.1038/hr.2008.25Search in Google Scholar PubMed
37. Chang T, Wu L. Methylglyoxal, oxidative stress, and hypertension. Can J Physiol Pharmacol 2006;84:1229–38.10.1139/y06-077Search in Google Scholar PubMed
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;19:95–100.10.3346/jkms.2004.19.1.95Search in Google Scholar PubMed PubMed Central
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;19:1819–25.10.1097/00004872-200110000-00016Search in Google Scholar PubMed
40. Ward RA, McLeish KR. Methylglyoxal: a stimulus to neutrophil oxygen radical production in chronic renal failure? Nephrol Dial Transplant 2004;19:1702–7.10.1093/ndt/gfh271Search in Google Scholar PubMed
©2014 by Walter de Gruyter Berlin Boston
Articles in the same Issue
- Masthead
- Masthead
- Review
- The relationship between oxidative stress and exercise
- Original articles
- Testosterone promotes glucose intolerance, lipid disorder and oxidative stress in type 1 diabetic rats
- Inhibition of key enzymes linked to type 2 diabetes and sodium nitroprusside-induced lipid peroxidation in rat pancreas by water-extractable phytochemicals from unripe pawpaw fruit (Carica papaya)
- Influence of gallic acid on oxidative stress-linked streptozotocin-induced pancreatic dysfunction in diabetic rats
- The evaluation of the hypoglycemic effect of soft drink leaf extract of Phyllanthus amarus (Euphorbiaceae) in rats
- Antioxidant activities for superoxide dismutase in patients with Crohn’s disease
- Resveratrol for prenatal-stress-induced oxidative damage in growing brain and its consequences on survival of neurons
- Hepatoprotective role of kaempferol during alcohol- and ΔPUFA-induced oxidative stress
- Evaluation of antiulcerogenic potential of antioxidant α-tocopherol in pylorus-ligated albino rats
- Comparison of the penetration and passage of Streptococcus mutans and Aggregatibacter actinomycetemcomitans through membranes loaded with tetracycline, amoxicillin, and chlorhexidine: an in vitro study
- Sodium-hydrogen exchanger inhibitory potential of Malus domestica, Musa × paradisiaca, Daucus carota, and Symphytum officinale
- Methylglyoxal causes endothelial dysfunction: the role of endothelial nitric oxide synthase and AMP-activated protein kinase α
- Reversal of alcohol induced testicular hyperlipidemia by supplementation of ascorbic acid and its comparison with abstention in male guinea pigs
- A cross-sectional study of surveillance of adverse drug reactions in inpatient departments of a tertiary care hospital
Articles in the same Issue
- Masthead
- Masthead
- Review
- The relationship between oxidative stress and exercise
- Original articles
- Testosterone promotes glucose intolerance, lipid disorder and oxidative stress in type 1 diabetic rats
- Inhibition of key enzymes linked to type 2 diabetes and sodium nitroprusside-induced lipid peroxidation in rat pancreas by water-extractable phytochemicals from unripe pawpaw fruit (Carica papaya)
- Influence of gallic acid on oxidative stress-linked streptozotocin-induced pancreatic dysfunction in diabetic rats
- The evaluation of the hypoglycemic effect of soft drink leaf extract of Phyllanthus amarus (Euphorbiaceae) in rats
- Antioxidant activities for superoxide dismutase in patients with Crohn’s disease
- Resveratrol for prenatal-stress-induced oxidative damage in growing brain and its consequences on survival of neurons
- Hepatoprotective role of kaempferol during alcohol- and ΔPUFA-induced oxidative stress
- Evaluation of antiulcerogenic potential of antioxidant α-tocopherol in pylorus-ligated albino rats
- Comparison of the penetration and passage of Streptococcus mutans and Aggregatibacter actinomycetemcomitans through membranes loaded with tetracycline, amoxicillin, and chlorhexidine: an in vitro study
- Sodium-hydrogen exchanger inhibitory potential of Malus domestica, Musa × paradisiaca, Daucus carota, and Symphytum officinale
- Methylglyoxal causes endothelial dysfunction: the role of endothelial nitric oxide synthase and AMP-activated protein kinase α
- Reversal of alcohol induced testicular hyperlipidemia by supplementation of ascorbic acid and its comparison with abstention in male guinea pigs
- A cross-sectional study of surveillance of adverse drug reactions in inpatient departments of a tertiary care hospital
