Lipoprotein(a), Oxidized Phospholipids, and Vascular Smooth Muscle Cell Phenotype and Viability
Abstract
Genetic studies have shown elevated plasma lipoprotein(a) (Lp(a)) levels to be an independent and causal risk factor for atherosclerotic cardiovascular disease and calcific aortic valve disease, however a definite mechanism for this pathogenicity has yet to be clearly identified. Oxidized phospholipids (oxPLs) have been implicated in facilitating atherogenic changes in the gene expression of vascular cells. As the primary carrier of oxPLs in the plasma, we hypothesize that Lp(a) contributes to vascular diseases by its enhanced ability to bind to and deliver oxPLs to tissue through a strong lysine binding site on its apolipoprotein(a) (apo(a)) component. Using a cultured primary coronary artery vascular smooth muscle cell (VSMC) model, we examined the effects of low-density lipoprotein (LDL), Lp(a) and apo(a) with or without this strong lysine binding site for OxPL addition on VSMC phenotype and viability. High concentrations of oxPLs were shown to induce atherogenic changes in VSMC gene expression and viability. However, likely due to inherent properties of our model, we were not able to show that physiologically relevant concentrations of Lp(a), apo(a) or LDL influenced VSMC gene expression. This study was the first to show that Lp(a) is capable of inducing expression of the apoptotic protein Bax in a cultured human coronary artery SMC model. This was not seen in cells treated with LDL, indicating that Lp(a) is uniquely cytotoxic to SMCs, likely due to its enhanced oxPL carrying capacity.