Effects of PCSK9 inhibitors on atherogenesis biomarkers in stimulated human coronary artery endothelial cells, correlation between PCSK9 and lipoprotein (A), and as independent predictors for coronary artery disease in premature CAD patients / Rahayu Zulkapli

• Main Author: Zulkapli, Rahayu
• Format: Thesis
• Language: English
• Published: 2024
• Subjects: QM Human anatomy; Biomedical engineering
• Online Access: https://ir.uitm.edu.my/id/eprint/102188/1/102188.pdf; https://ir.uitm.edu.my/id/eprint/102188/
• Institution: Universiti Teknologi Mara

Coronary artery disease (CAD) is the leading cause of death worldwide and has a strong link to familial hypercholesterolemia (FH). FH is an autosomal dominant lipoprotein metabolic condition that causes an increase in LDL-c levels and an elevated risk of premature CAD (pCAD). Elevation of proprotein convertase subtilisin/kexin type 9 (PCSK9) level in pCAD patients may contribute to the initiation of atherogenesis by an increase in inflammation. One of the gene mutations present in FH involves a gain-of-function point mutation in PCSK9. Individuals with FH are more likely to have high Lp(a) levels than the general population. Despite extensive research, the underlying mechanism by which Lp(a) mediates atherogenesis and inflammation is still incompletely understood. The release of PCSK9 during inflammation in atherosclerosis suggests that, in addition to the elevation of Lp(a), a potential correlation could exist between Lp(a) and PCSK9. Targeting Lp(a) and PCSK9 might provide an additive benefit beyond LDL-c lowering. The anti-atherogenic properties of PCSK9 inhibitors on atherogenesis biomarkers via PCSK9 reduction have yet to be established. Hence, this study aimed to (1) investigate the enhancement of PCSK9 production by LPS and Lp(a)-stimulation in human coronary artery endothelial cells (HCAEC), (2) determine the pleiotropic effects of PCSK9 inhibitors in LPS and (3) Lp(a)-stimulated HCAEC on atherogenesis biomarkers, and monocyte endothelial cell binding capacity, (4) explore the correlation and association between Lp (a) and PCSK9, and (5) determine the role of Lp(a) and PCSK9 as independent predictors for CAD in pCAD patients. This study was divided into two parts, in vitro and human studies. For the in vitro study, the stimulation effects on PCSK9 production, followed by the determination of pleiotropic effects of PCSK9 inhibitors on atherogenesis biomarkers were determined using ELISA (protein), QuantiGene Plex 96-well (gene), and monocyte binding capacity. For human studies, pCAD (with and without clinically diagnosed FH) and normal controls (NC) were subjected to blood samples to analyse Lp(a) and PCSK9 concentrations.