Modulation of atherogenesis biomarkers by PCSK9 inhibitors in Lp(a)-stimulated human coronary artery endothelial cells.

BACKGROUND

Atherosclerosis is a complex inflammatory disease driven by endothelial dysfunction. However, most in vitro studies rely on lipopolysaccharide (LPS) or oxidized LDL (oxLDL) as stimulants, overlooking the pathogenic role of lipoprotein(a) [Lp(a)]. Lp(a) is an independent and genetically determined risk factor for cardiovascular disease (CVD), but its precise mechanisms in promoting endothelial activation, inflammation, and monocyte adhesion remain poorly understood. The underlying mechanisms remain unclear despite clinical evidence that PCSK9 inhibitors (PCSK9i) lower plasma Lp(a) levels. This study explores the critical role of Lp(a) in driving PCSK9 expression and atherogenesis biomarkers, evaluates the protective effects of PCSK9i on endothelial activation, dysfunction and inflammation in Lp(a)-stimulated human coronary artery endothelial cells (HCAECs), and investigates their potential to mitigate monocyte adhesion, a key process in early atherogenesis.

METHODOLOGY

HCAECs were stimulated with Lp(a) and treated with Alirocumab or Evolocumab. Cell viability was assessed using the MTS assay. The expression of PCSK9, inflammatory (IL-6, NF-κB p65), endothelial activation (E-selectin, ICAM-1), and endothelial function (eNOS) biomarkers were quantified using ELISA and QuantiGene plex assays. Monocyte adhesion to endothelial cells was measured using the Rose Bengal method.

RESULTS

Lp(a) stimulation increased PCSK9, IL-6, ICAM-1, E-selectin, NF-κB p65, and reduced eNOS in HCAECs. Both Alirocumab and Evolocumab lowered PCSK9 protein levels, with Alirocumab showing more potent effects. Evolocumab consistently reduced PCSK9 gene expression, whereas Alirocumab elicited variable effects. IL-6 and NF-κB p65 were elevated by both inhibitors, especially Alirocumab. Both treatments reduced ICAM-1 and E-selectin proteins, but gene expression varied. eNOS expression improved only at high concentrations (100 µg/ml), particularly with Evolocumab. Monocyte adhesion decreased at lower doses of both inhibitors, suggesting protective effects against early atherogenesis.

CONCLUSION

PCSK9i exhibits pleiotropic effects beyond lipid-lowering by modulating endothelial activation, inflammation, and monocyte adhesion in Lp(a)-stimulated HCAECs. These findings provide mechanistic insights into the potential atheroprotective properties of PCSK9i, highlighting their role in early atherogenesis prevention.

CLINICAL TRIAL NUMBER

Not applicable.