Coronary heart disease (CHD), a type of cardiovascular disease (CVD), is the leading cause of morbidity and mortality in developed countries. CHD is characterised by the myocardium being undersupplied with blood and oxygen, most commonly due to plaques forming in the lumen of the coronary arteries. This obstructs blood flow and causes myocardial ischemia. One of the most significant risk factors for the development of CHD are high levels of low-density lipoprotein cholesterol (LDL-C). Consequently, therapies that lower its concentration are the gold standard in CVD treatment. In recent years, proprotein convertase subtilisin/kexin type 9 (PCSK9) has become a crucial therapeutic target in therapies aimed at reducing LDL-C as PCSK9 promotes the degradation of the low-density lipoprotein receptor (LDLR). Consequently, this is reflected in elevated LDL-C levels in the blood. By inhibiting the degradation of LDLR, PCSK9 inhibitors lower LDL-C levels in the blood. Thus, they are proving to be an optimistic way to reduce hyperlipidaemias.
This master's thesis aims to determine the differences in gene expression, potential PCSK9 coregulators, in patients with CHD before and after a six-month treatment with PCSK9 inhibitors, compared to healthy subjects. Measurements were carried out on complementary DNA (cDNA) samples previously obtained from ribonucleic acid (RNA) isolated from the subjects’ the peripheral blood. The quantitative polymerase chain reaction (qPCR) method was optimized in order to measure the expression of four genes: SREBP1, SREBP2, LDLR, and LIPC. These genes encode proteins that act as coregulators of PCSK9.
The results pointed to a difference in the expression of the SREBP2, LDLR, and LIPC genes in CHD patients compared to healthy subjects, with statistically significantly lower SREBP2 gene expression and statistically significantly higher LDLR and LIPC gene expression in CHD patients compared to healthy subjects. The findings also suggested that treatment with PCSK9 inhibitors affects the expression of the SREBP2 and LIPC genes. After six months of treatment, the expression of the SREBP2 gene was statistically markedly higher, while the expression of the LIPC gene was significantly lower compared to the pre-treatment baseline expression. No statistically significant variation in the expression of genes encoding PCSK9 coregulators was found between the two groups of patients receiving different types of PCSK9 inhibitors. Since the link between the genes examined in this study and how they affect the regulation of PCSK9 and therefore the development of CHD is currently still under-researched, it is difficult to draw general conclusions based on the results of the present study. To gain a clearer insight into how the PCSK9 inhibitors affect the expression of genes co-regulating the PCSK9 enzyme and the subsequent changes in the lipid profile, future research should be aimed at determining whether changes in the lipid profile resulting from treatment with PCSK9 inhibitors are associated with changes in the expression of the genes examined in this master’s thesis.
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