PCSK9: A key modulator of cardiovascular health.
V.G. Athyros, Aristotle University, Hippocration Hospital, Thessaloniki, Greece
In 2003 research led to the discovery of the ninth and the last member of the family, known as PC subtilisin kexin, the PCSK9. In animal studies PCSK9 protein found to be expressed mainly in the liver, adult hepatocytes, and less in the small intestine and kidney, adrenals, and transiently expressed in the developing central nervous system. Due to the great expression of the cells of the liver and because of the detection of the gene of PCSK9 on human chromosome 1p32, a region that is associated with familial hypercholesterolemia (FH) in some families, soon led to the confirmation that the gain of function (GOF) mutations of the PCSK9gene is the third (however very rare) cause of familial hypercholesterolaemia (FH), with the loss of function (LOF) mutations of the LDL receptor (LDLR) and that of apolipoprotein B (ApoB) being the other two causes. The PCSK9 is a protein synthesized in the form of a pre-protein in the endoplasmic reticulum of cells. There are two routes through which the PCSK9 affects the activity of LDL receptors. The extracellular route where PCSK9 secreted from hepatocytes associate with LDLR, the complex PCSK9-LDLR enters the hepatocytes and this is leads to the degradation of the LDLR by lysosomes. The existence and function of PCSK9 is a negative feed-back mechanism ensuring that the LDLR will not reduce LDL particles of the blood for ever.The normal mechanism suggests that the LDLR in connected to an LDL particle,accompanies it intracellular where this is degraded providing intracellular cholesterol esters (useful in the synthesis of cellular membranes, production of hormones adrenal and gonadal and composition of bile from the liver), while LDLR is recycled to the cell surface. This happensfor approximately 150 times with each LDLR and then this is degraded by PCSK9. If this was not so, the LDLR would remove LDL-C from the plasma continuously, resulting eventually to very low or zero LDL levels, which is not desirable, because cholesterol esters within normal range is useful and its complete absence is not compatible with life (homozygous familial abetalipoproteinemia).Experimentally this was evident in complete inactivation (knockout) of the gene PCSK9 in mice liver. These showed severe hypocholesterolaemia, with about 40% and 80% decrease in total cholesterol and LDL-C, respectively.
Aberrations or malfunction of PCSK9 may cause or alleviate problems of lipoprotein metabolism. Recent studies,during the last 10 years, showed the relationship of PCSK9 levels and function with cardiovascular disease (CVD) and the cardiovascular health.
Mutations that lead to loss of function of the gene PCSK9 (LOF) result in significantly lower levels of LDL-C (Figure 1 and 2) resulting in alifelong reduction in cardiovascular events up to 88% in humans. Conversely, mutations leading to increased gene function of PCSK9 (GOF) result in significantly higher levels of LDL-C (FH - Figure 1 and 2), which are related to a significant increase in cardiovascular events due to progression of atherosclerosis and increased cardiovascular risk. PCSK9 levels in plasma are elevated not only in patients with FH, but also in patients with familial combined hypercholesterolemia. This suggests that rare mutations of PCSK9 can aggravate the clinical phenotype of the patients carrying mutations of LDLR. Similarly, the APOE genotype can affect the lipid phenotype of PCSK9 mutations as suggested in at least one study, with particular emphasis on genotype E3/E2.
Moreover, it appears that PCSK9 targets besides LDLR, and the receptors of VLDL particles (VLDLR) and receptors of apoprotein E (ApoER). Also recently, it was shown that PCSK9 may reduce the lipoprotein receptor-related protein 1 (LRP1) in various cells. Finally, CD36, the scavenger receptor with multiple ligands of cellular functions, including facilitating of cellular uptake of free fatty acids (FFA), may be affected by PCSK9, at least in intestinal epithelial cells and adipocytes.
Like the liver, adrenal glands toohave the need of cholesterol synthesis and uptake of cholesterol from the blood for appropriate function. It was found that Annexin A2 is a natural inhibitor of extrahepatic PCSK9, and that the Anxa2-nockout mice, express very high levels of PCSK9 plasma which dramatically reduced levels of LDLR, of adrenal glands, the intestine, but not of the liver.
With regard to age and gender, a recent pediatric study, which included 1,700 participants, revealed that in boys, plasma levels of PCSK9 fell continuously from age 9 to 16 years, fully consistent with the average levels of total cholesterol. In contrast, in girls, PCSK9 levels peaked at age 13 and then decreased to a greater extent than at 16 years old boys with a corresponding effect on cholesterol levels.
All the above show that PCSK9 plays a key role in the homeostasis of cholesterol and modulates significantly the cardiovascular risk. People with high levels of PCSK9 or GOF mutations have elevated plasma levels of LDL-C and significantly increased risk of cardiovascular disease during their lifetime. People with low levels of PCSK9 or LOF mutations have reduced levels of plasma LDL-C and significantly lower risk of developing cardiovascular disease. Treatment with statins results in elevated plasma PCSK9 but reduces LDL-C by other mechanisms. This suggests that the decrease in PCSK9 levels can enhance the efficacy of statins and further reduce LDL-C levels.
Figure 1
Figure 2
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