Abstract
Cardiovascular disease (CVD) is one of the leading causes of death worldwide. Atherosclerosis is characterized by the progressive formation of lipid plaques within blood vessel walls which eventually occlude the vessel lumen and block blood flow. Elevated concentrations of lipoprotein(a) [Lp(a)] are an independent risk factor for developing atherosclerosis and CVD. Lp(a) consists of a low-density lipoprotein like particle that is covalently linked to a unique glycoprotein apolipoprotein(a).
Lp(a) possesses both atherogenic and thrombogenic properties. Lp(a) accumulates oxidised phospholipids (OxPL) from cell membranes of other lipoproteins and promotes lipid deposition and inflammation in the artery. Unfortunately, to date, there is no effective therapy available to lower Lp(a) or reduce these atherogenic properties of Lp(a). Riboceine is a cysteine analogue designed to increase synthesis of the antioxidant glutathione (GSH) by releasing L-cysteine, the precursor of GSH synthesis. This project aims to evaluate the potential of riboceine as a novel therapy to lower Lp(a) and increase GSH synthesis. As GSH is an essential cofactor for the reduction of OxPL, it may also reduce the OxPL content of Lp(a); thereby reduce atherogenicity of Lp(a). As OxPL are involved in the regulation of cholesterol levels, riboceine may also alter plasma cholesterol levels.
This study showed that riboceine is not an ideal intervention for lowering Lp(a) levels as it reduces Lp(a) formation only by 15-20% and only at very high concentrations. Riboceine was shown to have no effect on already formed Lp(a). Riboceine showed a trend of increase in both plasma and liver GSH levels in vivo, indicating that riboceine may act as a promising therapeutic to increase GSH levels. Moreover, riboceine showed a trend of decrease in total plasma cholesterol levels in vivo. These results suggest that riboceine may increase GSH levels which could alter Lp(a) atherogenicity as well as reduce cholesterol levels, thus lowering the risk of atherosclerosis and heart disease.
Future studies will require an increased sample size for both GSH and cholesterol studies in vivo. In addition, it will be required to measure cell membrane and Lp(a) OxPL content to confirm our hypothesis.