Abstract
Cardiovascular diseases are the leading cause of mortality worldwide, averaging over 32% of all global deaths. The development of cardiovascular diseases is primarily initiated by atherosclerosis, a process of artery narrowing due to a widespread accumulation of cholesterol or other fatty substances. While there are lifestyle changes that could slow down the progression of the disease, lipoprotein(a) [Lp(a)] remains to be a major independent risk factor for the development of atherosclerotic cardiovascular disease. There are currently no FDA-approved pharmaceuticals to reduce Lp(a) levels, although several compounds are in clinical trials.
The liver is the primary organ for Lp(a) catabolism, with hepatocytes being the main cell line as they express a wide array of “classical” and unconventional lipoprotein receptors. One of those subtypes, plasminogen receptor with a C-terminal lysine (PlgRKT), has been recently implicated in a novel Lp(a) clearance pathway. Limited evidence regarding the tandem interaction of Annexin A2/S100A10 with Lp(a) exists as well. The pharmacological relevance of plasminogen receptors has been reinforced by several publications outlining the use of cytokines, M-CSF and IFN-gamma, in the upregulation of PlgRKT expression in immune cells.
This project investigated the effect of M-CSF and IFN-gamma on Lp(a) uptake and the expression of three main plasminogen receptors in HepG2 cells. The findings have demonstrated that both treatments increase the expression of PlgRKT, which is believed to be the main contributor to increasing the uptake of Lp(a). Evidence suggests that M-CSF and IFN-gamma are specific inducers of PlgRKT, as the expression levels of S100A10 and Annexin A2 are not affected. The findings of this study will aid the collective understanding of Lp(a) clearance pathways via plasminogen receptors and lay the foundations for future Lp(a)-lowering therapies.