Deo Nikita, Siddiqui Halima, Peppercorn Katie, Madani Golnoush, Rutherford-Blyth Alexandria, Rutledge Malcolm, Williams Michael J A, McCormick Sally P A, Redpath Gregory M I
Department of Biochemistry, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand; HeartOtago, University of Otago, Dunedin, New Zealand.
HeartOtago, University of Otago, Dunedin, New Zealand; Department of Medicine, Otago Medical School, University of Otago, Dunedin, New Zealand.
J Lipid Res. 2025 Aug 25;66(10):100889. doi: 10.1016/j.jlr.2025.100889.
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, sertraline, fluoxetine, and paroxetine, we found that citalopram and paroxetine stimulated Lp(a) uptake. Imipramine and citalopram enhanced cell surface binding of Lp(a) to increase uptake by macropinocytosis. Consistent with imipramine and citalopram boosting extracellular serotonin levels, serotonin itself also enhanced Lp(a) surface binding and uptake. In contrast to Lp(a), imipramine and citalopram had no effect on low-density lipoprotein (LDL) 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 SSRIs such as citalopram and paroxetine 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.
我们最近发现，纤溶酶原受体通过巨胞饮作用调节脂蛋白(a)[Lp(a)]的质膜结合和摄取。在本研究中，我们试图进一步明确脂蛋白(a)[Lp(a)]的巨胞饮作用，发现抗抑郁药和血清素在这一过程的调节中发挥了意想不到的作用。我们发现三环类抗抑郁药丙咪嗪增强了Lp(a)的摄取，这与其作为巨胞饮作用抑制剂的已发表作用相矛盾。将这些实验扩展到常用的血清素摄取抑制剂（SSRI）西酞普兰、舍曲林、氟西汀和帕罗西汀，我们发现西酞普兰和帕罗西汀刺激了Lp(a)的摄取。丙咪嗪和西酞普兰增强了Lp(a)与细胞表面的结合，以增加通过巨胞饮作用的摄取。与丙咪嗪和西酞普兰提高细胞外血清素水平一致，血清素本身也增强了Lp(a)的表面结合和摄取。与Lp(a)不同，丙咪嗪和西酞普兰对低密度脂蛋白（LDL）的摄取没有影响。丙咪嗪和血清素增加了具有C末端赖氨酸的纤溶酶原受体（PlgRKT）的表达，该受体已知可增强Lp(a)与细胞表面的结合，这可能解释了它们对Lp(a)摄取的影响。最后，丙咪嗪和西酞普兰增加了Lp(a)向Rab11回收内体的转运，但没有增加其在细胞内的降解途径。这些发现表明，西酞普兰和帕罗西汀等SSRI可能对患有抑郁症且Lp(a)水平通常升高、心血管疾病风险增加的患者具有降低Lp(a)的潜在治疗作用。
