Targeting the Proprotein Convertase Subtilisin/Kexin Type 9 for the Treatment of Dyslipidemia and Atherosclerosis

Abstract

Hypercholesterolemia is a major risk factor for cardiovascular diseases, increasing the incidence of myocardial infarction and death. Statin-induced lowering of low-density lipoprotein cholesterol (LDL-C) reduces cardiovascular morbidity and mortality. However, many individuals treated with statins do not achieve their target levels of LDL-C, and thus, LDL-associated residual risk remains. Gain-of-function mutations of the proprotein convertase subtilisin/kexin type 9 (PCSK9) are associated with hypercholesterolemia and increased risk of cardiovascular events. Conversely, loss-of-function mutations are linked to low plasma LDL-C levels and a reduction of cardiovascular risk without known unwanted effects on individual health. Experimental studies have revealed that PCSK9 reduces the hepatic uptake of LDL-C by increasing the endosomal and lysosomal degradation of LDL receptors (LDLR). Low intracellular cholesterol levels in response to statin treatment activate the sterol regulatory element-binding protein-2 (SREBP-2), resulting in coexpression of LDLR and PCSK9. Although this self-regulatory mechanism contributes to maintain cholesterol homeostasis preventing excessive cholesterol uptake, it may limit the therapeutic effect of statins. A number of clinical studies have demonstrated that inhibition of PCSK9 alone and in addition to statins potently reduces serum LDL-C concentrations. Moreover, experimental studies indicate that PCSK9 might accelerate atherosclerosis by promoting inflammation, endothelial dysfunction, and hypertension by mechanisms independent of the LDLR. Further research is needed to characterize the potential therapeutic and to rule out unwanted off-target effects of PCSK9 inhibition. In this review we elucidate the role of PCSK9 in lipid homeostasis, highlight the impact of PCSK9 on atherosclerosis, and summarize current therapeutic strategies targeting PCSK9.

The Relationship between the Plasma PCSK9 Levels and Platelet Indices in Patients with Stable Coronary Artery Disease

“…(PCSK9), a serine protease synthesized primarily in the liver, is a newly-identified member that plays a key role in lipid metabolism and atherosclerosis 6) , and also in inflammation and cancer 7,8) . Emerging evidence has shown that the plasma PCSK9 levels could be considered as an easy-to-measure and promising marker of clinical interest, given the clinical relevance of a higher plasma PCSK9 level to multiple cardiometabolic risk factors in different populations 9) and the recent findings that the PCSK9 levels predict recurrent cardiovascular events in patients with stable CAD, even in those with well-controlled low density lipoprotein cholesterol (LDL-C) levels 10) .…”

“…It is possible that the complex interactions among dyslipidemia, inflammation, sensitive plasma molecules and platelet aggregation in association with atherosclerosis and metabolic syndrome should be taken into careful consideration. First, PCSK9, a novel target for hypercholesterolemia, plays a well-established and essential role in cholesterol homeostasis via enhancing the endosomal and lysosomal degradation of LDL-receptor (LDLR), resulting in increased LDL-C levels 6) . Positive correlations have been found between plasma the PCSK9 and LDL-C levels in subjects of diverse ethnicities, including European-Americans, Hispanics, African-Americans, and more recently, Han Chinese populations 9) .…”

New Era of Lipid-Lowering Drugs

“…The existence of PCSK9 was first reported by Seidah et al (2003), when it was identified as proprotein convertase neural apoptosis-regulated convertase 1. Since then, there has been an explosion of information about PCSK9, with more than 1000 articles being published, including several comprehensive reviews of its function, regulation, and the consequences of its inhibition (Horton et al, 2009;Catapano and Papadopoulos, 2013;Poirier and Mayer, 2013;Urban et al, 2013;Seidah et al, 2014;Stawowy, 2015).…”

Antibodies to watch in 2014

“…10 Blocking the binding of PCSK9 to the receptors interferes with this degradation pathway and leads to reductions in serum LDL cholesterol levels. As of November 1, 2013, three mAbs targeting PCSK9, alirocumab, evolocumab, and bococizumab, are undergoing evaluation in Phase 3 studies.…”