title: Proprotein convertase subtilisin/kexin 9 inhibitors: an emerging lipid-lowering therapy?
abstract: Proprotein convertase subtilisin/kexin 9 (PCSK9) is part of the proteinase K subfamily of subtilases and plays a key role in lipid metabolism. It increases degradation of the low-density lipoprotein receptor (LDL-R), modulates cholesterol metabolism and transport, and contributes to the production of apolipoprotein B (apoB) in intestinal cells. Exogenous PCSK9 modifies the activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and acyl coenzyme A:cholesterol acyltransferase and enhances secretion of chylomicrons by modulating production of lipids and apoB-48. Statins increase PCSK9 messenger RNA expression and attenuate the capacity to increase LDL-R levels. Therefore, the inhibition of PCSK9 in combination with statins provides a promising approach for lowering low-density lipoprotein cholesterol (LDL-C) concentrations. This review will address new therapeutic strategies targeting PCSK9, including monoclonal antibodies, antisense oligonucleotides, small interfering RNAs, and other small molecule inhibitors. Further studies are still needed to determine the efficacy and safety of the PCSK9 inhibitors not only to decrease LDL-C but also to investigate the potential underlying mechanisms involved and to test whether these compounds actually reduce cardiovascular end points and mortality.
authors.affiliation: Department of Cardiology, University of Medicine and Pharmacy "Victor Babes" Timisoara, Timisoara, Romania Center for Interdisciplinary Research, University of Medicine and Pharmacy "Victor Babes" Timisoara, Timisoara, Romania.
authors.forename: Simona
authors.initials: S
authors.lastname: Dragan
authors.affiliation: Center for Interdisciplinary Research, University of Medicine and Pharmacy "Victor Babes" Timisoara, Timisoara, Romania Department of Functional Sciences, Chair of Pathophysiology, University of Medicine and Pharmacy "Victor Babes" Timisoara, Timisoara, Romania dr.corinaserban@yahoo.com.
authors.forename: Maria-Corina
authors.initials: MC
authors.lastname: Serban
authors.affiliation: Department of Hypertension, Chair of Nephrology and Hypertension, Medical University of Lodz, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Banach
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D008078:Cholesterol, LDL / Q000097:blood*; D002986:Clinical Trials as Topic; D006801:Humans; D050356:Lipid Metabolism; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors* / Q000502:physiology; D011973:Receptors, LDL / Q000502:physiology; D012697:Serine Endopeptidases / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D016376:Oligonucleotides, Antisense; D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C577155:evolocumab
keywords: PCSK9; low-density lipoprotein receptor; proprotein convertase subtilisin/kexin 9; statins