Effect of erythromycin on homocysteine-induced extracellular matrix metalloproteinase-2 production in cultured rat vascular smooth muscle cells.

BACKGROUND & OBJECTIVE: Several lines of evidence have shown an association between Chlamydia infection and atherosclerosis, but clinical trials of preventive antibiotic (erythromycin) treatment in patients with coronary artery disease have shown conflicting results. Hyperhomocysteinaemia is an independent risk factor of coronary artery disease and causes an intense remodelling of the extracellular matrix in arterial walls, particularly an elastolysis involving metalloproteinases. In the present study we investigated the effects of erythromycin on the production of homocysteineinduced extracellular matrix metalloproteinase-2 (MMP-2) in cultured rat vascular smooth muscle cells (VSMCs). METHODS: Effects of different concentration of homocysteine (Hcy) (0-5000 micromol/l) on MMP-2 production, and the effects of different erythromycin concentrations (0-10 mmol/l) on homocysteine-induced MMP-2 production in cultured rat VSMCs were studied using gelatin zymography and Western blotting. The changes of MMP-2 under various treatments for 1, 3 and 5 days were also compared. RESULTS: Homocysteine (50-1000 mu mol/l) increased the production of MMP-2 significantly in a dose-dependent manner and reduced the production of MMP-2 at a high level (5000 mu mol/l). Increased production of MMP-2 induced by homocysteine was reduced by extracellularly added erythromycin in a dose-dependent manner. INTERPRETATION & CONCLUSION: Homocysteine increased the production of MMP-2 significantly in a dose-dependent manner. Extracellularly added erythromycin decreased homocysteine-induced MMP-2 secretion. The findings of the present study suggested that the beneficial effect of erythromycin on vascular disease processes might be due to its inhibitory effect on the Hcyinduced production of MMP-2 in VSMCs.

Hyperhomocysteinaemia & folic acid supplementation in patients with high risk of coronary artery disease.

BACKGROUND & OBJECTIVES: Many traditional independent risk factors such as diabetes mellitus, hypertension, hypercholesterolaemia, smoking, male sex, old age, etc., contribute to the development of coronary artery disease (CAD). Hyperhomocysteinaemia is an independent risk factor of CAD but the role of plasma homocysteine (Hcy) in high risk patients (> or = 3 risk factors) is not known. We investigated the role of plasma Hcy, folic acid, vitamin B12 in patients with high risk (> or = 3 risk factors) of CAD and effects of supplementation of folic acid in the patients with hyperhomocysteinaemia. METHODS: The plasma Hcy levels in 152 patients with > or = 3 risk factors of CAD and 136 patients with 1-2 risk factors and 48 individuals with no risk factors were measured using high performance liquid chromatography (HPLC) with fluorescence detection. Plasma folic acid and vitamin B12 levels were also measured in these patients with immunoassays. The patients with hyperhomocysteinaemia were treated with 5 mg of folic acid for 8 wk, and plasma levels of Hcy were measured after treatment. RESULTS: The plasma Hcy level was significantly higher in the patients with > or = 3 risk factors of CAD than in those with 1-2 risk factors and controls. The plasma levels of folic acid and vitamin B12 were significantly lower in the patients with > or = 3 risk factors of CAD compared to those with 1-2 risk factors and controls. The Hcy levels in the patients with > or = 3 risk factors of CAD significantly reduced by 33.5 per cent after 8 wk folic acid administration. INTERPRETATION & CONCLUSION: Plasma Hcy level was elevated significantly in patients with > or = 3 risk factors of CAD. Hyperhomocysteinaemia appears to play an important role in the pathogenesis of CAD. Folic acid supplementation may be useful in reducing plasma Hcy level in high risk patients with hyperhomocysteinaemia.