doi: 10.1161/CIRCULATIONAHA.105.562058
(Circulation. 2005;112:e266.)
© 2005 American Heart Association, Inc.
Correspondence |
Letter Regarding Article by Becker et al, "Hyperhomocysteinemia, a Cardiac Metabolic Disease: Role of Nitric Oxide and the p22phox Subunit of NADPH Oxidase"
A’ Cardiology Department, Athens University Medical School, Hippokration Hospital, Athens, Greece
Becker et at1 examined the effect of experimental homocysteinemia on the nitric oxide (NO)–dependent control of cardiac O2 consumption and enzymatic sources of superoxide. They found that methionine-induced experimental homocysteinemia inhibits NO-dependent regulation of cardiac O2 consumption and increases the p22phox subunit of NADPH oxidase. Although the findings are extremely interesting, extrapolations to clinical homocysteinemia must be made with caution, because this experimental model is characterized by enhanced superoxide production due to NO synthase uncoupling, in part as a result of the increase in levels of asymmetrical dimethylarginine (ADMA).2 Previous studies showed that in animal models, methionine increases ADMA as a result of (1) the free radical–induced impairment of dimethylarginine dimethylaminohydrolase (DDAH), the enzyme responsible for ADMA metabolism,3 and (2) the enhanced conversion of homocysteine to methionine, which drives the formation of ADMA through a respective increase in N-methyltransferase activity.4 However, we5 have recently shown that although methionine-induced homocysteinemia in humans is associated with endothelial dysfunction, in part due to the rapid elevation of ADMA, this pathway is not activated in chronic homocysteinemia, which explains why ADMA levels are normal in homocysteinemic patients. Chronic homocysteinemia is characterized by accumulation of homocysteine due to enzymatic insufficiency but is not accompanied by increased methionine levels. Therefore, although the administration of methionine in healthy animals (or humans) may lead to an artificial elevation of homocysteine, it also activates biochemical pathways (such as arginine transmethylation) that normally are inactive in chronic homocysteinemia, and it probably influences the expression of a number of genes, which raises questions about its usefulness as a model of chronic homocysteinemia.
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1. Becker JS, Adler A, Schneeberger A, Huang H, Wang Z, Walsh E, Koller A, Hintze TH. Hyperhomocysteinemia, a cardiac metabolic disease: role of nitric oxide and the p22phox subunit of NADPH oxidase. Circulation. 2005; 111: 2112–2118.
2. Cooke JP. Asymmetrical dimethylarginine: the Uber marker? Circulation. 2004; 109: 1813–1818.
3. Ito A, Tsao PS, Adimoolam S, Kimoto M, Ogawa T, Cooke JP. Novel mechanism for endothelial dysfunction: dysregulation of dimethylarginine dimethylaminohydrolase. Circulation. 1999; 99: 3092–3095.
4. Boger RH, Sydow K, Borlak J, Thum T, Lenzen H, Schubert B, Tsikas D, Bode-Boger SM. LDL cholesterol upregulates synthesis of asymmetrical dimethylarginine in human endothelial cells: involvement of S-adenosylmethionine-dependent methyltransferases. Circ Res. 2000; 87: 99–105.
5. Antoniades C, Tousoulis D, Marinou, Carmen K, Vasiliadou C, Tentolouris C, Brilli S, Vlachopoulos C, Vlachopoulos C, Stefanadis C. The role of oxidative stress and asymmetric dimethylarginine (ADMA) in endothelial dysfunction and inflammatory cytokines expression, during methionine-induced homocysteinemia. J Am Coll Cardiol. 2005; 45: 430A. Abstract.
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