State-of-the-Art Paper
Targeting the Proprotein Convertase Subtilisin/Kexin Type 9 for the Treatment of Dyslipidemia and Atherosclerosis

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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.

Key Words

atherosclerosis
LDL cholesterol
LDL receptor
PCSK9
proprotein convertase subtilisin/kexin type 9

Abbreviations and Acronyms

ARH
autosomal recessive hypercholesterolemia protein
EGF-A
epidermal growth factor-like repeat homology domain
ENaC
epithelial (Na+) channel
LDL-C
low-density lipoprotein cholesterol
LDLR
low-density lipoprotein receptor
PCSK9
proprotein convertase subtilisin/kexin type 9
siRNA
small interfering RNA
SREBP
sterol regulatory element-binding protein
VLDLR
very low-density lipoprotein receptor

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Drs. Böhm and Laufs are supported by Deutsche Forschungsgemeinschaft (KFO 196). Drs. Urban, Böhm, and Laufs are supported by the Deutsche Gesellschaft für Kardiologie. Dr. Böhm is a member of the advisory boards of Medtronic, Servier, and Boehringer Ingelheim; and has received honoraria from Medtronic, St. Jude Medical, Boehringer Ingelheim, Servier, Bristol-Myers Squibb, and Pfizer. Dr. Laufs has received lecture fees from Merck, Sharp & Dohme, Roche, and Sanofi. Dr. Pöss has reported that he no relationships relevant to the contents of this paper to disclose.