Antidepressants stimulate lipoprotein(a) macropinocytosis via serotonin-enhanced cell surface binding

We recently found that plasminogen receptors regulate the plasma membrane binding and uptake of Lp(a) via macropinocytosis. In this study, we sought to further define lipoprotein(a) [Lp(a)] macropinocytosis, discovering an unexpected role for antidepressants and serotonin in the regulation of this process. We found that the tricyclic antidepressant imipramine enhanced Lp(a) uptake, in contradiction of its published role as a macropinocytosis inhibitor. Extending these experiments to the commonly used serotonin uptake inhibitors (SSRIs) citalopram and sertraline, we found that citalopram stimulated, while sertraline inhibited, Lp(a) uptake. Imipramine and citalopram enhanced cell surface binding of Lp(a) rather than upregulating macropinocytosis. Consistent with imipramine and citalopram boosting extracellular serotonin levels, serotonin itself also enhanced Lp(a) surface binding and uptake. Imipramine and serotonin increased expression of the plasminogen receptor with a C-terminal lysine (PlgRKT), a receptor known to enhance cell surface binding of Lp(a), likely accounting for their effects on Lp(a) uptake. Finally, imipramine and citalopram increased Lp(a) delivery into Rab11 recycling endosomes, but not degradative pathways in the cell. These findings indicate citalopram and imipramine may have utility as a potential Lp(a)-lowering therapeutic in people suffering from depression who often have elevated Lp(a) levels and an increased risk of cardiovascular disease.