Plasma homoarginine, arginine, asymmetric dimethylarginine and total homocysteine interrelationships in rheumatoid arthritis, coronary artery disease and peripheral artery occlusion disease
- 589 Downloads
Elevated circulating concentrations of total l-homocysteine (thCys) and free asymmetric dimethylarginine (ADMA) are long-established cardiovascular risk factors. Low circulating l-homoarginine (hArg) concentrations were recently found to be associated with increased cardiovascular morbidity and mortality. The biochemical pathways of these amino acids overlap and share the same cofactor S-adenosylmethionine (SAM). In the present study, we investigated potential associations between hArg, l-arginine (Arg), ADMA and thCys in plasma of patients suffering from rheumatoid arthritis (RA), coronary artery disease (CAD) or peripheral artery occlusive disease (PAOD). In RA, we did not find any correlation between ADMA or hArg and thCys at baseline (n = 100) and after (n = 83) combined add-on supplementation of omega-3 fatty acids, vitamin E, vitamin A, copper, and selenium, or placebo (soy oil). ADMA correlated with Arg at baseline (r = 0.446, P < 0.001) and after treatment (r = 0.246, P = 0.03). hArg did not correlate with ADMA, but correlated with Arg before (r = 0.240, P = 0.02) and after treatment (r = 0.233, P = 0.03). These results suggest that hArg, ADMA and Arg are biochemically familiar with each other, but unrelated to hCys in RA. In PAOD and CAD, ADMA and thCys did not correlate.
KeywordsCardiovascular risk Homoarginine Homocysteine Methylation Plasma Rheumatoid arthritis
Asymmetric dimethylarginine (N G,N G-dimethyl-l-arginine)
Coronary artery disease
Gas chromatography–mass spectrometry
Gas chromatography–tandem mass spectrometry
Nitric oxide synthase
Peripheral arterial occlusive disease
The authors are thankful to Bibiana Beckmann for excellent laboratory assistance.
Conflict of interest
The authors declare that they have no conflict of interest.
- Antoniades C, Tousoulis D, Marinou K, Vasiliadou C, Tentolouris C, Bouras G, Pitsavos C, Stefanadis C (2006) Asymmetrical dimethylarginine regulates endothelial function in methionine-induced but not in chronic homocystinemia in humans: effect of oxidative stress and proinflammatory cytokines. Am J Clin Nutr 84:781–788PubMedGoogle Scholar
- Choe CU, Atzler D, Wild PS, Carter AM, Böger RH, Ojeda F, Simova O, Stockebrand M, Lackner K, Nabuurs C, Marescau B, Streichert T, Muller C, Luneburg N, De Deyn PP, Benndorf RA, Baldus S, Gerloff C, Blankenberg S, Heerschap A, Grant PJ, Magnus T, Zeller T, Isbrandt D, Schwedhelm E (2013) Homoarginine levels are regulated by l-arginine:glycine amidinotransferase and affect stroke outcome: results from human and murine studies. Circulation 128:1451–1461CrossRefPubMedGoogle Scholar
- Crowson CS, Nicola PJ, Kremers HM, O’Fallon WM, Therneau TM, Jacobsen SJ, Roger VL, Ballman KV, Gabriel SE (2005) How much of the increased incidence of heart failure in rheumatoid arthritis is attributable to traditional cardiovascular risk factors and ischemic heart disease? Arthritis Rheum 52:3039–3044CrossRefPubMedGoogle Scholar
- Doshi S, McDowell I, Goodfellow J, Stabler S, Boger R, Allen R, Newcombe R, Lewis M, Moat S (2005) Relationship between S-adenosylmethionine, S-adenosylhomocysteine, asymmetric dimethylarginine, and endothelial function in healthy human subjects during experimental hyper- and hypohomocysteinemia. Metabolism 54(3):351–360CrossRefPubMedGoogle Scholar
- Kayacelebi AA, Pham VV, Willers J, Hahn A, Stichtenoth DO, Jordan J, Tsikas D (2014c) Plasma homoarginine (hArg) and asymmetric dimethylarginine (ADMA) in patients with rheumatoid arthritis: is homoarginine a cardiovascular corrective in rheumatoid arthritis, an anti-ADMA? Int J Cardiol 176:1129–1131CrossRefPubMedGoogle Scholar
- Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, McQueen MJ, Probstfield J, Fodor G, Held C, Genest J (2006) Heart outcomes prevention evaluation (HOPE) 2 investigators homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 354: 1567–1577Google Scholar
- Tsikas D, Schubert B, Gutzki FM, Sandmann J, Frölich JC (2003) Quantitative determination of circulating and urinary asymmetric dimethylarginine (ADMA) in humans by gas chromatography-tandem mass spectrometry as methyl ester tri(N-pentafluoropropionyl) derivative. J Chromatogr B 798:87–99CrossRefGoogle Scholar
- Tsikas D, Thum T, Becker T, Pham VV, Chobanyan K, Mitschke A, Beckmann B, Gutzki FM, Bauersachs J, Stichtenoth DO (2007) Accurate quantification of dimethylamine (DMA) in human urine by gas chromatography-mass spectrometry as pentafluorobenzamide derivative: evaluation of the relationship between DMA and its precursor asymmetric dimethylarginine (ADMA) in health and disease. J Chromatogr B 851:229–239CrossRefGoogle Scholar
- Valtonen P, Laitinen T, Lyyra-Laitinen T, Raitakari OT, Juonala M, Viikari JS, Heiskanen N, Vanninen E, Punnonen K, Heinonen S (2008) Serum l-homoarginine concentration is elevated during normal pregnancy and is related to flow-mediated vasodilatation. Circ J 72:1879–1884CrossRefPubMedGoogle Scholar