Low Whole-Blood S -Adenosylmethionine and Correlation Between 5-Methyltetrahydrofolate and Homocysteine in Coronary Artery Disease

Abstract

Mild elevation of plasma homocysteine is an independent risk factor for vascular disease. We studied the role of 5-methyltetrahydrofolate (5-MTHF), the folate form directly involved in homocysteine metabolism, in contrast to previous studies, which used total folate measurements, in 70 coronary artery disease (CAD) patients and control subjects. We also measured S-adenosylmethionine (SAM), which controls the activity of critical enzymes of homocysteine metabolism. Fasting plasma total homocysteine was elevated (> 12.4 mumol/L for women, > 13.3 mumol/L for men) in 17% of patients, in accordance with earlier studies. These patients showed lower 5-MTHF (12.4 +/- 1.0 mumol/L, mean +/- SD) than control subjects (24.2 +/- 15.0, P < .001), and there was a clear correlation (multiple linear regression analysis: P = .002) of this relevant form of folate with homocysteine. However, 37% of the normohomocysteinemic patients also revealed similarly low 5-MTHF levels, suggesting that a decrease of 5-MTHF does not necessarily cause hyperhomocysteinemia. SAM was significantly decreased in patients (1.4 +/- 0.4 mumol/L) compared with control subjects (1.8 +/- 0.3, P < .001) but was not correlated to homocysteine or 5-MTHF. The correlation between homocysteine and 5-MTHF that was found in CAD patients but not in control subjects confirms the direct relationship between these compounds in vivo. The new finding of low SAM in patients demands further studies, since it might indicate that low levels pose risk and that SAM might be a protective factor against the development of CAD.

Homocysteine Induces Protein Kinase C Activation and Stimulates c-Fos and Lipoprotein Lipase Expression in Macrophages

“…Hyperhomocysteinemia is an independent risk factor for cardiovascular disease (1)(2)(3)(4)(5). Although Hcys has been implicated in many biological events associated with atherogenesis, the mechanism(s) by which this amino acid exerts its proatherogenic effects is still not well known.…”

“…The high risk of cardiovascular disease in these individuals cannot be totally explained by classic risk factors. Hyperhomocysteinemia is an independent risk factor for cardiovascular disease in the general population (1)(2)(3)(4)(5). In the diabetic population, the association between hyperhomocysteinemia and cardiovascular disease seems even stronger (6 -10).…”

“…After removal of unbound proteins by washing of the columns with buffer B (20 mmol/l Tris [pH 7.5], 0.5 mmol/l EDTA, 0.5 mmol/l EGTA, and 10 mmol/l ␤-mercaptoethanol), fractions containing PKC were eluted with buffer C (Tris [pH 7.5], 0.5 mmol/l EDTA, 0.5 mmol/l EGTA, 10 mmol/l ␤-mercaptoethanol, and 0.2 mol/l NaCl). Eluates were analyzed for PKC activity, following the optimum conditions of the assay, by measuring the incorporation of 32 P into the synthetic peptide Ac-myelin basic protein (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). The specificity of the assay was determined by subtracting the radioactivity obtained in the presence of the pseudosubstrate inhibitor PKC(19-36) from total radioactivity.…”

Polymorphism of the Methionine Synthase Gene

“…In another report, the significant correlation between homocysteine and 5-methyltetrahydrofolate, a substrate for methionine synthase whose metabolism is regulated by MTHFR, was reported in patients with coronary artery disease. 31 Low levels of 5-methyltetrahydrofolate may lead to elevated homocysteine owing to lack of sufficient substrate for methionine synthase. Taken together with these findings, our results indicate that genetic variation of MTHFR likely has a greater influence on the remethylation pathway than does genetic variation of methionine synthase.…”

Analysis of Plasma Homocysteine Levels in Patients with Unstable Angina

“…Two metaanalyses of retrospective studies confirm these findings [22][23][24][25][26][27][28][29][30][31] . Homocysteine may be considered a risk factor, as may smoking 32,33 , hypertension [32][33][34] , dyslipidemia 31,35,36 , and hyperglycemia 37 ; it seems, however, to be an independent factor 38,39 .…”