Aaptamine Counteracts Statin-Induced PCSK9 Elevation to Improve LDL Receptor Expression and Cholesterol Uptake

Abstract

Atherosclerosis arises from lipid accumulation and plaque formation, primarily driven by elevated levels of LDL-cholesterol (LDL-C). PCSK9 plays a critical role by degrading LDL receptors (LDL-R), which are responsible for the clearance of LDL-C from the bloodstream. Consequently, inhibiting PCSK9 represents a promising strategy to enhance LDL-R expression and promote LDL-C uptake. Statins are commonly used to treat high cholesterol by decreasing the production of cholesterol. However, they also raise PCSK9 levels, which may explain why some patients don't respond as well as they should to statins. Aaptamines, marine alkaloids with notable structural diversity and bioactivity, are known to regulate gene transcription. This study aimed to evaluate the effects of aaptamine in mitigating the statin-induced increase in PCSK9 expression, LDL-R levels, and LDL-C uptake. Cytotoxicity was assessed using the MTS assay for simvastatin, aaptamine, and their combination. PCSK9 mRNA levels were quantified by real-time PCR, while protein expression was analyzed via western blotting. Immunohistochemistry was employed to assess LDL-R levels and LDL-C uptake in liver cells. The results demonstrated that simvastatin significantly upregulated PCSK9 gene expression. However, co-treatment with aaptamine reduced PCSK9 expression by 94–61%. Additionally, aaptamine enhanced LDL-R protein levels and LDL-C uptake by 3.21-fold in cells co-treated with simvastatin. These results suggest that aaptamine lowers the rise in PCSK9 caused by statins and raises the expression of LDL-R, which helps liver cells get rid of LDL-C.