共 90 条
PCSK9 inhibition for the treatment of hypercholesterolemia: Promises and emerging challenges
被引:34
作者:

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Tibolla, Gianpaolo
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机构:
Univ Milan, Dept Pharmacol & Biomol Sci, I-20133 Milan, Italy
IRCCS Multimed, Milan, Italy Univ Milan, Dept Pharmacol & Biomol Sci, I-20133 Milan, Italy

Catapano, Alberico Luigi
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Univ Milan, Dept Pharmacol & Biomol Sci, I-20133 Milan, Italy
IRCCS Multimed, Milan, Italy Univ Milan, Dept Pharmacol & Biomol Sci, I-20133 Milan, Italy
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.
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页码:103 / 111
页数:9
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机构:
Univ Lille Nord France, Lille, France
INSERM, U859, Lille, France CHU Hotel Dieu, CHU Nantes, Clin Endocrinol, Inst Thorax, F-44093 Nantes, France

Krempf, Michel
论文数: 0 引用数: 0
h-index: 0
机构:
INSERM, U915, F-44000 Nantes, France
Univ Nantes, Fac Med, Inst Thorax, F-44000 Nantes, France CHU Hotel Dieu, CHU Nantes, Clin Endocrinol, Inst Thorax, F-44093 Nantes, France

Pattou, Francois
论文数: 0 引用数: 0
h-index: 0
机构:
Univ Lille Nord France, Lille, France
INSERM, U859, Lille, France CHU Hotel Dieu, CHU Nantes, Clin Endocrinol, Inst Thorax, F-44093 Nantes, France

Costet, Philippe
论文数: 0 引用数: 0
h-index: 0
机构:
INSERM, U915, F-44000 Nantes, France CHU Hotel Dieu, CHU Nantes, Clin Endocrinol, Inst Thorax, F-44093 Nantes, France

Cariou, Bertrand
论文数: 0 引用数: 0
h-index: 0
机构:
CHU Hotel Dieu, CHU Nantes, Clin Endocrinol, Inst Thorax, F-44093 Nantes, France
INSERM, U915, F-44000 Nantes, France
Univ Nantes, Fac Med, Inst Thorax, F-44000 Nantes, France CHU Hotel Dieu, CHU Nantes, Clin Endocrinol, Inst Thorax, F-44093 Nantes, France
[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

Le May, Cedric
论文数: 0 引用数: 0
h-index: 0
机构:
CHU Nantes, INSERM, U915, F-44035 Nantes 01, France CHU Nantes, INSERM, U915, F-44035 Nantes 01, France

Kourimate, Sanae
论文数: 0 引用数: 0
h-index: 0
机构:
CHU Nantes, INSERM, U915, F-44035 Nantes 01, France CHU Nantes, INSERM, U915, F-44035 Nantes 01, France

Langhi, Cedric
论文数: 0 引用数: 0
h-index: 0
机构:
CHU Nantes, INSERM, U915, F-44035 Nantes 01, France CHU Nantes, INSERM, U915, F-44035 Nantes 01, France

Chetiveaux, Maud
论文数: 0 引用数: 0
h-index: 0
机构:
CHU Nantes, INSERM, U915, F-44035 Nantes 01, France CHU Nantes, INSERM, U915, F-44035 Nantes 01, France

论文数: 引用数:
h-index:
机构:

Comera, Christine
论文数: 0 引用数: 0
h-index: 0
机构:
INSERM, U563, Toulouse, France
INRA, UR66, Paris, France CHU Nantes, INSERM, U915, F-44035 Nantes 01, France

Collet, Xavier
论文数: 0 引用数: 0
h-index: 0
机构:
INSERM, U563, Toulouse, France CHU Nantes, INSERM, U915, F-44035 Nantes 01, France

Kuipers, Folkert
论文数: 0 引用数: 0
h-index: 0
机构:
Univ Groningen, Ctr Liver Digest & Metab Dis, NL-9700 AB Groningen, Netherlands CHU Nantes, INSERM, U915, F-44035 Nantes 01, France

Krempf, Michel
论文数: 0 引用数: 0
h-index: 0
机构:
CHU Nantes, INSERM, U915, F-44035 Nantes 01, France
Univ Nantes, Inst Thorax, Clin Endocrinol & Nutr, Nantes, France
Ctr Rech Nutr Humaine Nantes, Nantes, France CHU Nantes, INSERM, U915, F-44035 Nantes 01, France

Cariou, Bertrand
论文数: 0 引用数: 0
h-index: 0
机构:
CHU Nantes, INSERM, U915, F-44035 Nantes 01, France
Univ Nantes, Inst Thorax, Clin Endocrinol & Nutr, Nantes, France CHU Nantes, INSERM, U915, F-44035 Nantes 01, France

Costet, Philippe
论文数: 0 引用数: 0
h-index: 0
机构:
CHU Nantes, INSERM, U915, F-44035 Nantes 01, France
Ctr Rech Nutr Humaine Nantes, Nantes, France CHU Nantes, INSERM, U915, F-44035 Nantes 01, France