PCSK9 inhibition for the treatment of hypercholesterolemia: Promises and emerging challenges

被引:34
作者
Norata, Giuseppe Danilo [1 ,2 ]
Tibolla, Gianpaolo [1 ,3 ]
Catapano, Alberico Luigi [1 ,3 ]
机构
[1] Univ Milan, Dept Pharmacol & Biomol Sci, I-20133 Milan, Italy
[2] Bossini Hosp, Soc Italiana Studio Aterosclerosi, Ctr Study Atherosclerosis, Cinisello Balsamo, Italy
[3] IRCCS Multimed, Milan, Italy
关键词
PCSK9; Hypercholesterolemia; LDL cholesterol; LDL receptor; Monoclonal antibodies; SUBTILISIN/KEXIN TYPE 9; DENSITY-LIPOPROTEIN RECEPTOR; PLASMA PROPROTEIN CONVERTASE; LDL RECEPTOR; FAMILIAL HYPERCHOLESTEROLEMIA; CHOLESTEROL-SYNTHESIS; APOLIPOPROTEIN-B; LIPID TRANSPORT; DEGRADATION; EXPRESSION;
D O I
10.1016/j.vph.2014.05.011
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Hypercholesterolemia, is a prominent risk factor for cardiovascular disease (CVD).Undestanding of the biochemical mechanisms that regulate the expression of the low density lipoproteins receptor (LDLR) and the hepatic clearance of LDL cholesterol (LDL-C) paved the way to the statin therapy as the gold standard for CVD prevention. The discovery of proteins that regulate - at a post-translational level - the activity of the LDLR has been a major breakthrough in developing new cholesterol-lowering drugs. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key modulator of the LDLR degradation in the liver. Genetic studies confirmed that in humans PCSK9 mutations associate with hypercholesterolemia and hypocholesterolemia (gain-of-function or loss-of-function variants respectively). Moreover, PCSK9 is up-regulated by statin treatment and limits the efficacy of these agents. These findings led to the development of PCSK9 inhibitors. Anti-PCSK9 monoclonal antibodies showed encouraging results and are currently being evaluated in phase III clinical trials. The aim of this short review is to describe the new frontier of PCSK9 inhibition in the treatment of hypercholesterolemia. Emphasis here is given to critical emerging issues linked to PCSK9 physiology and pharmacology, which will require future investigation to definitely address the potential of anti-PCSK9 drugs in clinical practice. (C) 2014 Elsevier Inc. All rights reserved.
引用
收藏
页码:103 / 111
页数:9
相关论文
共 90 条
[41]   PCSK9 regulates neuronal apoptosis by adjusting ApoER2 levels and signaling [J].
Kysenius, Kai ;
Muggalla, Pranuthi ;
Matlik, Kert ;
Arumae, Urmas ;
Huttunen, Henri J. .
CELLULAR AND MOLECULAR LIFE SCIENCES, 2012, 69 (11) :1903-1916
[42]   PCSK9 Impedes Hepatitis C Virus Infection In Vitro and Modulates Liver CD81 Expression [J].
Labonte, Patrick ;
Begley, Syntia ;
Guevin, Carl ;
Asselin, Marie-Claude ;
Nassoury, Nasha ;
Mayer, Gaetan ;
Prat, Annik ;
Seidah, Nabil G. .
HEPATOLOGY, 2009, 50 (01) :17-24
[43]   Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice [J].
Lagace, Thomas A. ;
Curtis, David E. ;
Garuti, Rita ;
McNutt, Markey C. ;
Park, Sahng Wook ;
Prather, Heidi B. ;
Anderson, Norma N. ;
Ho, Y. K. ;
Hammer, Robert E. ;
Horton, Jay D. .
JOURNAL OF CLINICAL INVESTIGATION, 2006, 116 (11) :2995-3005
[44]   Genetic and Metabolic Determinants of Plasma PCSK9 Levels [J].
Lakoski, Susan G. ;
Lagace, Thomas A. ;
Cohen, Jonathan C. ;
Horton, Jay D. ;
Hobbs, Helen H. .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2009, 94 (07) :2537-2543
[45]   Wild-type PCSK9 inhibits LDL clearance but does not affect apoB-containing lipoprotein production in mouse and cultured cells [J].
Lalanne, F ;
Lambert, G ;
Amar, MJA ;
Chétiveaux, M ;
Zaïr, Y ;
Jarnoux, AL ;
Ouguerram, K ;
Friburg, J ;
Seidah, NG ;
Brewer, HB ;
Krempf, M ;
Costet, P .
JOURNAL OF LIPID RESEARCH, 2005, 46 (06) :1312-1319
[46]   Plasma PCSK9 concentrations correlate with LDL and total cholesterol in diabetic patients and are decreased by fenofibrate treatment [J].
Lambert, Gilles ;
Ancellin, Nicolas ;
Charlton, Francesca ;
Comas, Daniel ;
Pilot, Julia ;
Keech, Anthony ;
Patel, Sanjay ;
Sullivan, David R. ;
Cohn, Jeffrey S. ;
Rye, Kerry-Anne ;
Barter, Philip J. .
CLINICAL CHEMISTRY, 2008, 54 (06) :1038-1045
[47]   Fasting induces hyperlipidemia in mice overexpressing proprotein convertase subtilisin kexin type 9: Lack of modulation of very-low-density lipoprotein hepatic output by the low-density lipoprotein receptor [J].
Lambert, Gilles ;
Jarnoux, Anne-Laure ;
Pineau, Thierry ;
Pape, Olivier ;
Chetiveaux, Maud ;
Laboisse, Christian ;
Krempf, Michel ;
Costet, Philippe .
ENDOCRINOLOGY, 2006, 147 (10) :4985-4995
[48]   Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Affects Gene Expression Pathways Beyond Cholesterol Metabolism in Liver Cells [J].
Lan, Hong ;
Pang, Ling ;
Smith, Marsha M. ;
Levitan, Diane ;
Ding, Wei ;
Liu, Li ;
Shan, Lixin ;
Shah, Vidhi V. ;
Laverty, Maureen ;
Arreaza, Gladys ;
Zhang, Qing ;
Murgolo, Nicholas J. ;
Hernandez, Marco ;
Greene, Jonathan R. ;
Gustafson, Eric L. ;
Bayne, Marvin L. ;
Davis, Harry R. ;
Hedrick, Joseph A. .
JOURNAL OF CELLULAR PHYSIOLOGY, 2010, 224 (01) :273-281
[49]   PCSK9 is expressed in pancreatic δ-cells and does not alter insulin secretion [J].
Langhi, Cedric ;
Le May, Cedric ;
Gmyr, Valery ;
Vandewalle, Brigitte ;
Kerr-Conte, Julie ;
Krempf, Michel ;
Pattou, Francois ;
Costet, Philippe ;
Cariou, Bertrand .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2009, 390 (04) :1288-1293
[50]   Proprotein Convertase Subtilisin Kexin Type 9 Null Mice Are Protected From Postprandial Triglyceridemia [J].
Le May, Cedric ;
Kourimate, Sanae ;
Langhi, Cedric ;
Chetiveaux, Maud ;
Jarry, Anne ;
Comera, Christine ;
Collet, Xavier ;
Kuipers, Folkert ;
Krempf, Michel ;
Cariou, Bertrand ;
Costet, Philippe .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2009, 29 (05) :684-U157