Back to Basics: PCSK9 as a New Target for the LDL Receptor

Abstract

Forty years after Goldstein and Brown's discovery of the low density lipoprotein receptor (LDLR)1 and 25 years after the introduction of the statins2, a cornerstone of the atherosclerotic disease management, the view of the scientific community studying the process of atherosclerosis turns once again to the LDLR through the action mechanism of proprotein convertase subtilisin/kexin type 9 (PCSK9)3. The assessment of genetic polymorphism with unexpected results in large studies revived the hypothesis about the important role of high density lipoprotein cholesterol (HDL-C) in lipoprotein metabolism4; the apparent eternal debate about the contribution of triglycerides (TG) and their remnants to the phenomenon of atherogenesis5. Such advances have lead to the re-prioritization of LDL management as a central and primary objective towards the prevention of the morbidity and mortality main cause in the Western world, atherosclerosis. Once again, we return to the discovery that led Goldstein and Brown to a Nobel Prize in 1985, the LDLR1; now seeking to avoid its degradation through the knowledge and understanding of PCSK9 action mechanism. Biochemical and molecular bases PCSK9, also called neural-apoptosis-regulated convertase 1 (NARC-1), is a serine protease, characterized by a three domain structure and a catalytic triad; it is the ninth member of the pro-protein convertase family3. The PCSK9 gene is located on chromosome 1p32.3 and is 22-kb in length, comprising 12 exons encoding a 692 amino acid glycoprotein. This convertase is highly expressed in liver, intestine and kidneys6. PCSK9 is synthesized as 74 kDa soluble zymogen (proPCSK9) which after an autocatalytic process within the endoplasmic reticulum, releases the pro-peptide (14kDa)-N terminal, resulting in a 60-kDa enzyme. This autoclivage process is necessary both towards its activation and release from the endoplasmic reticulum3. The autocatalytic process allows the progression through the secretory pathway and thus directly interacts with the LDLR. It is important to mention, that the catalytic activity, does not seems to be required for LDLR degradation, but only for the activation and secretion of PCSK9 6. This serine protease binds the epidermal growth factor domain A (EGF-A) on the LDLR, upon which both PCSK9 and LDLR are internalized by the hepatocyte to be finally degraded within the lysosome (Figure 1)6. Figure 1 PCSK9 regulates LDLR turnover through increased intracellular degradation. Past, present and future of PCSK9 Ten years ago, Abifadel et al. have reported 3 families in France with familial hypercholesterolemia associated with increased functionality and expression of PCSK9, with no alteration in the LDL receptor or apo B structure7. In 2005, two years later, Cohen et al. through the program/study Atherosclerosis Risk in Communities (ARIC) described the loss of PCSK9 function in African American and Caucasian individuals. In the past, they reported a prevalence of 2.6% in deficit of function, with concomitantly reduced serum levels of low density lipoprotein cholesterol LDL-C (28% lower) and CV events, such as myocardial infarction, need for cardiac bypass surgery and coronary deaths (88%). The latter, in turn, showed a decrease in PCSK9 expression of 3.2%, with an average LDL-C reduction of 15% vs. control groups and reduction of 47% in CV events requiring cardiac surgery and mortality related to this cause. Interestingly, in the ARIC study, 50% of subjects had hypertension, 30% were smokers and 20% had diabetes8. The inevitable comparison between the reduction on risk observed among individuals with a deficit of PCSK9 expression/function and the individuals evaluated in large studies with statins for 5 years (similar LDL-C decrease between the two groups with marked lower risk in patients with the genetic alteration), has led to the development of different strategies to silence this serin protease and thus, increase LDLR levels in the liver, with a consequent decrease of circulating LDL-C levels. The early intervention might magnify the clinical efficacy of cholesterol-lowering therapy by attenuating the development and progression of atherosclerosis. Therapeutic groups primarily involved in this strategy, would be those with familial hypercholesterolemia, statin-intolerance and perhaps patients with a very high cardiovascular risk with failure to meet the targets through the existing pharmacological armamentarium. It also necessary to determine whether PCSK9 affects only LDL-C levels, or whether it may also exert a direct action on the vasculature and other structures. Its interaction/interplay with cholesterol ester transfer protein (CETP) and with the cholesterol efflux mediated by HDL-C is also yet to be determined. Despite an undoubtedly interesting mechanism of action, several questions remain: the safety of PCSK9 combination with statins, the immune response to PCSK9 antibodies after a prolonged treatment, the real value of the pleiotropic effects that statins show and finally, the potential interactions with others enzymes and proteases.