Effect of folic acid and vitamin B[12] supplementation on isoprenaline induced myocardial infarction, endothelial dysfunction and atherothrombosis in experimental hyperhomocysteinemic rats

ABSTRACT

Elevated total plasma homocysteine [tHcy] concentration is an independent risk factor for ischemic heart disease and other vascular disorders. Treatment with vitamins [folic acid and B12] has shown to reduce plasma homocysteine level but it is not clear to what extent such treatment may reduce clinical vascular events or mortality. The aim of the present study was to evaluate hyperhomocysteinemia as a risk factor of isoprenaline induced myocardial infarction [MI], endothelial dysfunction and hypercoagulable state and to examine the effect of folic acid either alone or in combination with vitamin B[12] on the experimentally induced myocardial infarction and to evaluate the effect of such vitamin treatment on the biomarkers of endothelial dysfunction and hypercoagulable state in post-methionine load hyperhomocysteinemic rats. Hyperhomocysteinemia [Hhcy] was induced in rats by daily intake of methionine [1g/kg b.wt.] in the drinking water for 4 weeks. MI was then induced by subcutaneous injection of isoprenaline in a dose of 85mg/kg b.wt/day for two days. Serum marker enzymes, creatine kinase [CK] and lactate dehydrogenase [LDH] were measured. Lipid peroxidation was measured as malondialdehyde [MDA] and reduced glutathione [GSH] concentrations in heart tissue. Plasma concentrations of von Willebrand factor [vWF] and D-dimer as markers of endothelial dysfunction and prothrombotic state were measured either in the experimental untreated hyperhomocysteinemic rats or in the treated ones. Hhcy resulted in a significant increase in serum CK and LDH levels. Cardiac MDA was significantly increased while GSH was significantly decreased in Hhcy group compared to the normal control group, plasma concentrations of vWF and D-dimer were also significantly increased. Serum marker enzymes and markers of cardiac oxidative stress were greatly exaggerated in Hhcy rats treated with isoprenaline in comparison with isoprenaline group. Administration of folic acid [10mg/kg, b.wt orally via gavage] alone and in combination with vitamin B[12] [500 ug/kg b.wt. i.m], concurrently for 4 weeks during the induction of Hhcy markedly reduced the increase in serum CK and LDH as well as the plasma concentration of vWF and D-dimer. Cardiac MDA content was decreased while cardiac GSH was elevated in the treated group compared to untreated Hhcy rats. These results suggest that Hhcy aggravates MI via oxidative stress mechanisms and that Hhcy may impair endothelial function and increases the biomarkers of prothrombotic state Treatment with either folic acid alone or in combination with vitamin B[12] can ameliorate the detrimental effects of Hhcy, reduce the risk of MI, appears to improve endothelial dysfunction and decrease plasma concentration of biomarkers of hypercoagulability. This provides preliminary evidence that such vitamin supplementation may have beneficial cardiovascular effects. However clinical benefit of vitamin supplementation has not yet been demonstrated and clinical trials are urgently required