Homocysteine as a Risk Factor for Vascular Disease

Abstract

An increased plasma homocysteine level is an independent risk factor for vascular disease. However, the pathological mechanisms by which homocysteine promotes atherosclerosis are not yet clearly defined. Arterial smooth muscle cells cultured in the presence of homocysteine grew to a higher density and produced and accumulated collagen at levels significantly above control values. Homocysteine concentrations as low as 50 mumol/L significantly increased both cell density and collagen production. Cell density increased by as much as 43% in homocysteine-treated cultures. Homocysteine increased collagen production in a dose-dependent manner. Smooth muscle cells treated with homocysteine at concentrations observed in patients with hyperhomocysteinemia had collagen synthesis rates as high as 214% of control values. Likewise, collagen accumulation in the cell layer was nearly doubled in homocysteine-treated cultures. Addition of aquacobalamin to homocysteine-treated cultures controlled the increase in smooth muscle cell proliferation and collagen production. These results indicate a cellular mechanism for the atherogenicity of homocysteine and provide insight into a potential preventive treatment.

Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease

“…Lesions were rich in smooth muscle cells and collagen, a result consistent with the ability of homocysteine to stimulate SMC proliferation and extracellular matrix deposition. 116 The effects of the hyperhomocysteinemic diets on lesion size and frequency were seen following 3 months, but not 12 months, of dietary treatment, suggesting that HHcy mainly influences the early stages of atherogenesis. Hoffman et al 28 also found significant increases in atherosclerotic lesion area in apoE-deficient mice fed a high methionine diet, compared to mice fed control diet.…”

Impaired Homocysteine Metabolism and Atherothrombotic Disease

“…In addition to this attack, which might be caused by homocysteinylation of the vascular wall proteins by homocysteine and/or its oxidized products (homocysteic acid, homocysteine sulfinic acid, and homocysteine thiolactone), in vitro and in vivo work suggests that reduced homocysteine can inhibit endothelial cell turn-over (Wang et al, 1997) and promote smooth muscle cell proliferation (Lubec et al, 1996b;Majors et al, 1997;Tsai et al, 1994Tsai et al, , 1996. Wang et al (1997) reported that low concentrations of homocysteine (10 to 50 mol/L) specifically inhibit the growth of endothelial cells.…”

Mild hyperhomocysteinaemia is associated with increased aortic stiffness in general population

“…It was reported, that homocysteine gradually increased collagen synthesis in vascular smooth muscle cells culture (VSMC) and was accompanied by an excessive accumulation of insoluble collagen in the cell layer, indicating the impaired collagen degradation. 4,5 Charpiot et al 6 reported, that dietary-induced hyperhomocysteinaemia in minipig decreased, subsequently, the elastin content and increased metalloproteinase-dependent elastolysis in abdominal aorta and coronary arteries. The link between collagen/elastin metabolism and homocysteine could be a hypothetical explanation of differential effect on central and peripheral artery stiffness.…”

“…1 There are several potential vascular consequences of elevated tHcy. Besides well-evident effect on coagulation, oxidative status and endothelial dysfunction, 2 several experimental studies reported that elevated tHcy can induce smooth muscle proliferation, collagen synthesis and deterioration of the elastic structures of the vessel wall, [3][4][5][6] a phenomenon resulting in increased stiffness of vessel wall.…”