A constantly elevated level of plasma cholesterol is a primary driver of atherosclerosis, leading to cardiovascular diseases that remain a leading cause of global mortality. While statins are widely prescribed to manage hypercholesterolaemia, their clinical utility is frequently limited by adverse side effects and a counterproductive induction of Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) expression. PCSK9 is a hepatic enzyme responsible for directing LDL-receptor (LDL-R)/LDL-cholesterol (LDL-C) complexes towards lysosomal degradation, preventing the receptor from recycling back to the surface of liver cells, thus reducing the uptake of circulating LDL-C. Therefore, PCSK9 offers a potential target for small-molecule inhibitors that block the function of this enzyme. In addition to the role of liver LDL-R in reducing circulating LDL-C levels, a hallmark of atherosclerotic lesions is also represented by the presence of macrophage-derived foam cells. Their formation is governed by the balance between oxidised LDL (oxLDL) influx, primarily mediated by CD36, and lipid efflux via ABCA1 and ABCG1. Therapeutic strategies that modulate these pathways may, therefore, attenuate foam cell development and atherosclerosis. Utilising molecular-based high-throughput screening platforms, our research has identified promising marine-derived therapeutic candidates. Notably, the marine alkaloid aaptamine reduces hepatic PCSK9 expression to enhance LDL receptor abundance and LDL-C uptake in human hepatic cells. Interestingly, the compound also exerts direct, multi-targeted regulatory effects at the cellular level within atherosclerotic lesions. Specifically, aaptamine acts beyond the liver to simultaneously decrease oxidised LDL (oxLDL) uptake in macrophages by downregulating influx receptors such as CD36, and, enhance cholesterol efflux in foam cells via the upregulation of ABCA1 and ABCG1. Furthermore, in vivo study demonstrates that marine-based natural product reduces plasma cholesterol levels. In conclusion, aaptamine and related marine-derived bioactive agents may represent a promising new class of therapeutic candidates either as monotherapy or in synergistic combination with statins to slow the progression of atherosclerosis.

Keywords. atherosclerosis,  aaptamine , PCSK9, statin, LDL-C