A more recent version of this article appeared on July 20, 2001

This Article Full Text Full Text (PDF) All Versions of this Article: 89/2/187    most recent hh1401.093459v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chambers, J. C. Articles by Kooner, J. S. Search for Related Content PubMed Articles by Chambers, J. C. Articles by Kooner, J. S. Related Collections Endothelium/vascular type/nitric oxide Mechanism of atherosclerosis/growth factors

(Circulation Research. 2001;0:hh1401.093459.)
© 2001 American Heart Association, Inc.

Article

Investigation of Relationship Between Reduced, Oxidized, and Protein-Bound Homocysteine and Vascular Endothelial Function in Healthy Human Subjects

John C. Chambers, Per M. Ueland, Melissa Wright, Caroline J. Doré, Helga Refsum Jaspal S. Kooner

From the National Heart and Lung Institute (J.C.C., J.S.K.) and the Department of Medical Statistics and Evaluation (M.W.), Imperial College School of Medicine, Hammersmith Hospital, London, UK; the Department of Pharmacology (P.M.U., H.R.), University of Bergen, Armauer Hansen Hus, Bergen, Norway; and the MRC Clinical Trials Unit (C.J.D.), London, UK.

Correspondence to Dr J.S. Kooner, MD, FRCP, Consultant Cardiologist, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK. E-mail j.kooner{at}ic.ac.uk

Abstract

Abstract—Previous studies investigating homocysteine and vascular disease have relied on total plasma homocysteine as the sole index of homocysteine status. We examined the dynamic relationship between vascular endothelial function and concentrations of total, protein-bound oxidized, free oxidized, and reduced homocysteine to identify the homocysteine form associated with endothelial dysfunction in humans. We investigated 14 healthy volunteers (10 men, 4 women). Brachial artery flow–mediated dilatation was measured at baseline and at 30, 60, 120, 240, and 360 minutes after oral (1) L-methionine (50 mg/kg), (2) L-homocysteine (5 mg/kg), and (3) placebo. Plasma concentrations of total, protein-bound oxidized, free oxidized, and reduced homocysteine were measured at each time point, and nitroglycerin-induced dilatation at was assessed at 0, 120, and 360 minutes. Flow-mediated dilatation fell, and concentrations of total, protein-bound oxidized, free oxidized, and reduced homocysteine increased after oral homocysteine and oral methionine (all P<0.05 for difference in time course compared with placebo). Flow-mediated dilatation showed a reciprocal relationship with reduced homocysteine during both homocysteine and methionine loading. In both loading studies, peak reduction in flow-mediated dilatation coincided with maximal reduced homocysteine concentrations. In contrast, there was no consistent relationship between flow-mediated dilatation and free oxidized homocysteine, protein-bound oxidized homocysteine, or related species. Nitroglycerin-induced dilatation was unchanged by oral homocysteine and oral methionine (P>0.10 compared with placebo). Reduced homocysteine is closely associated with endothelial dysfunction during oral methionine and oral homocysteine loading. Our observations support the hypothesis that reduced homocysteine is the deleterious form of homocysteine for vascular function in vivo and suggest a less important role for other homocysteine species.

Key Words: homocysteine • endothelium • atherosclerosis • redox • nitric oxide

This article has been cited by other articles:

				R. Priora, D. Summa, S. Frosali, A. Margaritis, D. Di Giuseppe, C. Lapucci, F. Ieri, F. M. Pulcinelli, A. Romani, F. Franconi, et al. Administration of Minor Polar Compound-Enriched Extra Virgin Olive Oil Decreases Platelet Aggregation and the Plasma Concentration of Reduced Homocysteine in Rats J. Nutr., January 1, 2008; 138(1): 36 - 41. [Abstract] [Full Text] [PDF]

				M. Rahmani, R. P. Cruz, D. J. Granville, and B. M. McManus Allograft Vasculopathy Versus Atherosclerosis Circ. Res., October 13, 2006; 99(8): 801 - 815. [Abstract] [Full Text] [PDF]

				A. Sciacqua, A. Scozzafava, A. Pujia, R. Maio, F. Borrello, F. Andreozzi, M. Vatrano, S. Cassano, M. Perticone, G. Sesti, et al. Interaction between vascular dysfunction and cardiac mass increases the risk of cardiovascular outcomes in essential hypertension Eur. Heart J., May 1, 2005; 26(9): 921 - 927. [Abstract] [Full Text] [PDF]

				M. L. Bots, J. Westerink, T. J. Rabelink, and E. J.P. de Koning Assessment of flow-mediated vasodilatation (FMD) of the brachial artery: effects of technical aspects of the FMD measurement on the FMD response Eur. Heart J., February 2, 2005; 26(4): 363 - 368. [Abstract] [Full Text] [PDF]

				M. E. Suliman, P. Barany, K. Kalantar-Zadeh, B. Lindholm, and P. Stenvinkel Homocysteine in uraemia--a puzzling and conflicting story Nephrol. Dial. Transplant., January 1, 2005; 20(1): 16 - 21. [Full Text] [PDF]

				S. J. Moat, S. N. Doshi, D. Lang, I. F. W. McDowell, M. J. Lewis, and J. Goodfellow Treatment of coronary heart disease with folic acid: is there a future? Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H1 - H7. [Full Text] [PDF]

				C. N. Roybal, S. Yang, C.-W. Sun, D. Hurtado, D. L. Vander Jagt, T. M. Townes, and S. F. Abcouwer Homocysteine Increases the Expression of Vascular Endothelial Growth Factor by a Mechanism Involving Endoplasmic Reticulum Stress and Transcription Factor ATF4 J. Biol. Chem., April 9, 2004; 279(15): 14844 - 14852. [Abstract] [Full Text] [PDF]

				R. Glowacki and H. Jakubowski Cross-talk between Cys34 and Lysine Residues in Human Serum Albumin Revealed by N-Homocysteinylation J. Biol. Chem., March 19, 2004; 279(12): 10864 - 10871. [Abstract] [Full Text] [PDF]

				M. Schachter, A. Raziel, S. Friedler, D. Strassburger, O. Bern, and R. Ron-El Insulin resistance in patients with polycystic ovary syndrome is associated with elevated plasma homocysteine Hum. Reprod., April 1, 2003; 18(4): 721 - 727. [Abstract] [Full Text] [PDF]

				B. Rosengarten, S. Osthaus, D. Auch, and M. Kaps Effects of Acute Hyperhomocysteinemia on the Neurovascular Coupling Mechanism in Healthy Young Adults Stroke, February 1, 2003; 34(2): 446 - 451. [Abstract] [Full Text] [PDF]

				A. De Bree, W. M. M. Verschuren, D. Kromhout, L. A. J. Kluijtmans, and H. J. Blom Homocysteine Determinants and the Evidence to What Extent Homocysteine Determines the Risk of Coronary Heart Disease Pharmacol. Rev., December 1, 2002; 54(4): 599 - 618. [Abstract] [Full Text] [PDF]

				N. Weiss, C. Keller, U. Hoffmann, and J. Loscalzo Endothelial dysfunction and atherothrombosis in mild hyperhomocysteinemia Vascular Medicine, August 1, 2002; 7(3): 227 - 239. [Abstract] [PDF]

				J. D. Symons, A. E. Mullick, J. L. Ensunsa, A. A. Ma, and J. C. Rutledge Hyperhomocysteinemia Evoked by Folate Depletion: Effects on Coronary and Carotid Arterial Function Arterioscler Thromb Vasc Biol, May 1, 2002; 22(5): 772 - 780. [Abstract] [Full Text] [PDF]