Abstract
Ribose-cysteine is a synthetic compound designed to increase glutathione (GSH) synthesis. Low levels of GSH and the GSH-dependent enzyme, glutathione peroxidase (GPx), is associated with cardiovascular disease (CVD) in both mice and humans. Here we investigate the effect of ribose-cysteine on GSH, GPx, oxidised lipids and atherosclerosis development in apolipoprotein E-deficient (apoE-/-) mice. Female 12-week old apoE-/- mice (n = 15) were treated with 4-5 mg/day ribose-cysteine in drinking water for 8 weeks or left untreated. Blood and livers were assessed for GSH, GPx activity and 8-isoprostanes. Plasma alanine transferase (ALT) and lipid levels were measured. Aortae were quantified for atherosclerotic lesion area in the aortic sinus and brachiocephalic arch and 8-isoprostanes measured. Ribose-cysteine treatment significantly reduced ALT levels (p<0.0005) in the apoE-/- mice. Treatment promoted a significant increase in GSH concentrations in the liver (p<0.05) and significantly increased GPx activity in the liver and erythrocytes of apoE-/-mice (p<0.005). The level of 8-isoprostanes were significantly reduced in the livers and arteries of apoE-/- mice (p<0.05 and p<0.0005, respectively). Ribose-cysteine treatment showed a significant decrease in total and low density lipoprotein (LDL) cholesterol (p<0.05) with no effect on other plasma lipids with the LDL reduction likely through upregulation of scavenger receptor-B1 (SR-B1). Ribose-cysteine treatment significantly reduced atherosclerotic lesion area by >50% in both the aortic sinus and brachiocephalic branch (p<0.05). Ribose-cysteine promotes a significant GSH-based antioxidant effect in multiple tissues as well as an LDL-lowering response. These effects are accompanied by a marked reduction in atherosclerosis suggesting that ribose-cysteine might increase protection against CVD.
Highlights
Atherosclerosis is the disease process occurring in arteries underpinning the development of cardiovascular disease [1]
Oxidised phospholipids within lipoproteins trapped in the artery promote the activation and infiltration of monocytes that subsequently differentiate into pro-inflammatory macrophages which enable foam cell formation and atherosclerosis development (1)
Oxidised phospholipids are catabolised by glutathione peroxidase (GPx; E.C. 1.11.1.9), an enzyme that catalyses their reduction to lipid alcohols [7]
Summary
Atherosclerosis is the disease process occurring in arteries underpinning the development of cardiovascular disease [1]. The amount of oxidised phospholipids (OxPL) present on these atherogenic lipoproteins associates with vascular disease [5, 6]. Oxidised phospholipids within lipoproteins trapped in the artery promote the activation and infiltration of monocytes that subsequently differentiate into pro-inflammatory macrophages which enable foam cell formation and atherosclerosis development (1). A recent meta-analysis of the rs1050450 polymorphism in GPx1 which reduces its activity, is associated with increased CVD risk [11]. An age-related decline in the activity of GPx3, the extracellular form in plasma, has recently been reported to be associated with cardiovascular disease [12]. Low plasma levels of GSH have been reported in cardiovascular disease patients [14] and in animal models of atherosclerosis [15]
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