Inhibition of PCSK9: A novel approach for the treatment of dyslipidemia

Coronary Artery Disease

Volumn 25, Issue 4, 2014, Pages 353-359

  Stawowy, Philipp ^a   Just, Isabell A ^a   Kaschina, Elena ^b  

^a DEUTSCHES HERZZENTRUM BERLIN   (Germany)

^b CHARITÉ UNIVERSITÄTSMEDIZIN BERLIN   (Germany)

Author keywords

cardiovascular risk; coronary artery disease; low density lipoprotein cholesterol; low density lipoprotein receptor; proprotein convertase subtilisin kexin type

Indexed keywords

ALIROCUMAB; ENZYME INHIBITOR; EVOLOCUMAB; LOW DENSITY LIPOPROTEIN CHOLESTEROL; PROPROTEIN CONVERTASE SUBTILISIN KEXIN TYPE 9 INHIBITOR; UNCLASSIFIED DRUG; ANTILIPEMIC AGENT; BIOLOGICAL MARKER; PCSK9 PROTEIN, HUMAN; SERINE PROTEINASE; SERINE PROTEINASE INHIBITOR;

ARTICLE; CHOLESTEROL BLOOD LEVEL; CHOLESTEROL METABOLISM; CORONARY ARTERY DISEASE; DRUG MECHANISM; DRUG TARGETING; DYSLIPIDEMIA; GAIN OF FUNCTION MUTATION; GENE; HIGH RISK PATIENT; HUMAN; LOSS OF FUNCTION MUTATION; NONHUMAN; OUTCOME ASSESSMENT; PATIENT SAFETY; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROPROTEIN CONVERTASE SUBTILISIN KEXIN TYPE 9 GENE; ANIMAL; ANTAGONISTS AND INHIBITORS; BLOOD; DRUG DESIGN; ENZYMOLOGY; GENETICS; HYPERCHOLESTEROLEMIA; METABOLISM; RISK FACTOR; TREATMENT OUTCOME;

ANIMALS; BIOLOGICAL MARKERS; CHOLESTEROL, LDL; CORONARY ARTERY DISEASE; DRUG DESIGN; HUMANS; HYPERCHOLESTEROLEMIA; HYPOLIPIDEMIC AGENTS; PROPROTEIN CONVERTASES; RISK FACTORS; SERINE ENDOPEPTIDASES; SERINE PROTEINASE INHIBITORS; TREATMENT OUTCOME;

EID: 84899993254     PISSN: 09546928     EISSN: 14735830     Source Type: Journal    
DOI: 10.1097/MCA.0000000000000113     Document Type: Article

References (66)

1. Brown CD, Higgins M, Donato KA, Rohde FC, Garrison R, Obarzanek E, et al. Body mass index and the prevalence of hypertension and dyslipidemia. Obes Res 2000; 8:605-619
2. Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K, Adair-Rohani H, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease study 2010. Lancet 2012; 380:2224-2260
3. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995; 333:1301-1307
4. Ko DT,Wijeysundera HC, Yun L, Austin PC, Cantor WJ, Tu JV. Effectiveness of preprocedural statin therapy on clinical outcomes for patients with stable coronary artery disease after percutaneous coronary interventions. Circ Cardiovasc Qual Outcomes 2011; 4:459-466
5. Waters D, Higginson L, Gladstone P, Kimball B, Le May M, Boccuzzi SJ, et al. Effects of monotherapy with an HMG-CoA reductase inhibitor on the progression of coronary atherosclerosis as assessed by serial quantitative arteriography. The Canadian Coronary Atherosclerosis Intervention Trial. Circulation 1994; 89:959-968
6. Kizer JR, Madias C, Wilner B, Vaughan CJ, Mushlin AI, Trushin P, et al. Relation of different measures of low-density lipoprotein cholesterol to risk of coronary artery disease and death in a meta-regression analysis of largescale trials of statin therapy. Am J Cardiol 2010; 105:1289-1296
7. Kostis WJ, Cheng JQ, Dobrzynski JM, Cabrera J, Kostis JB. Meta-analysis of statin effects in women versus men. J Am Coll Cardiol 2012; 59: 572-582
8. Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a metaanalysis of data from 170 000 participants in 26 randomised trials. Lancet 2010; 376:1670-1681
9. Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, et al. ESC/EAS guidelines for the management of dyslipidaemias: the task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011; 32:1769-1818
10. Stone NJ, Robinson J, Lichtenstein AH, Bairey Merz CN, Lloyd-Jones DM, Blum CB, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013 [Epub ahead of print]. doi:10.1016/j.jacc. 2013.11.002
11. Waters DD, Brotons C, Chiang CW, Ferrieres J, Foody J, Jukema JW, et al. Lipid treatment assessment project I: lipid treatment assessment project 2: a multinational survey to evaluate the proportion of patients achieving lowdensity lipoprotein cholesterol goals. Circulation 2009; 120:28-34
12. Sathasivam S, Lecky B. Statin induced myopathy. BMJ 2008; 337:a2286
13. Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010; 375:735-742
14. Knopp RH. Drug treatment of lipid disorders. N Engl J Med 1999; 341:498-511
15. Seidah NG, Benjannet S,Wickham L, Marcinkiewicz J, Jasmin SB, Stifani S, et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc Natl Acad Sci USA 2003; 100:928-933
16. Thomas G. Furin at the cutting edge: from protein traffic to embryogenesis and disease. Nat Rev Mol Cell Biol 2002; 3:753-766
17. Kappert K, Meyborg H, Fritzsche J, Urban D, Kruger J, Wellnhofer E, et al. Proprotein convertase subtilisin/kexin type 3 promotes adipose tissue-driven macrophage chemotaxis and is increased in obesity. PloS One 2013; 8:e70542
18. Stawowy P, Meyborg H, Stibenz D, Borges Pereira Stawowy N, Roser M, Thanabalasingam U, et al. Furin-like proprotein convertases are central regulators of the membrane type matrix metalloproteinase-pro-matrix metalloproteinase-2 proteolytic cascade in atherosclerosis. Circulation 2005; 111:2820-2827
19. Brown MS, Goldstein JL. A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood. Proc Natl Acad Sci USA 1999; 96:11041-11048
20. Horton JD, Cohen JC, Hobbs HH. Molecular biology of PCSK9: its role in LDL metabolism. Trends Biochem Sci 2007; 32:71-77
21. Piper DE, Jackson S, Liu Q, Romanow WG, Shetterly S, Thibault ST, et al. The crystal structure of PCSK9: a regulator of plasma LDL-cholesterol. Structure 2007; 15:545-552
22. Awan Z, Seidah NG, MacFadyen JG, Benjannet S, Chasman DI, Ridker PM, et al. Rosuvastatin, proprotein convertase subtilisin/kexin type 9 concentrations, and LDL cholesterol response: the JUPITER trial. Clin Chem 2012; 58:183-189
23. Dubuc G, Tremblay M, Pare G, Jacques H, Hamelin J, Benjannet S, et al. A new method for measurement of total plasma PCSK9: clinical applications. J Lipid Res 2010; 51:140-149
24. Jeon H, Blacklow SC. Structure and physiologic function of the low-density lipoprotein receptor. Annu Rev Biochem 2005; 74:535-562
25. Maxwell KN, Breslow JL. Adenoviral-mediated expression of PCSK9 in mice results in a low-density lipoprotein receptor knockout phenotype. Proc Natl Acad Sci USA 2004; 101:7100-7105
26. Kwon HJ, Lagace TA, McNutt MC, Horton JD, Deisenhofer J. Molecular basis for LDL receptor recognition by PCSK9. Proc Natl Acad Sci USA 2008; 105:1820-1825
27. Park SW, Moon YA, Horton JD. Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver. J Biol Chem 2004; 279:50630-50638
28. Graham MJ, Lemonidis KM, Whipple CP, Subramaniam A, Monia BP, Crooke ST, Crooke RM. Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice. J Lipid Res 2007; 48:763-767
29. Cariou B, Le May C, Costet P. Clinical aspects of PCSK9. Atherosclerosis 2011; 216:258-265
30. Persson L, Henriksson P, Westerlund E, Hovatta O, Angelin B, Rudling M. Endogenous estrogens lower plasma PCSK9 and LDL cholesterol but not Lp(a) or bile acid synthesis in women. Arterioscler Thromb Vasc Biol 2012; 32:810-814
31. Persson L, Cao G, Stahle L, Sjoberg BG, Troutt JS, Konrad RJ, et al. Circulating proprotein convertase subtilisin kexin type 9 has a diurnal rhythm synchronous with cholesterol synthesis and is reduced by fasting in humans. Arterioscler Thromb Vasc Biol 2010; 30:2666-2672
32. Langhi C, Le May C, Kourimate S, Caron S, Staels B, Krempf M, et al. Activation of the farnesoid X receptor represses PCSK9 expression in human hepatocytes. FEBS Lett 2008; 582:949-955
33. Wen S, Jadhav KS,Williamson DL, Rideout TC. Treadmill exercise training modulates hepatic cholesterol metabolism and circulating PCSK9 concentration in high-fat-fed mice. J Lipids 2013; 2013:908048
34. Cariou B, Langhi C, Le Bras M, Bortolotti M, Le KA, Theytaz F, et al. Plasma PCSK9 concentrations during an oral fat load and after short term high-fat, high-fat high-protein and high-fructose diets. Nutr Metab 2013; 10:4
35. Dubuc G, Chamberland A, Wassef H, Davignon J, Seidah NG, Bernier L, et al. Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 2004; 24:1454-1459
36. Careskey HE, Davis RA, Alborn WE, Troutt JS, Cao G, Konrad RJ. Atorvastatin increases human serum levels of proprotein convertase subtilisin/kexin type 9. J Lipid Res 2008; 49:394-398
37. Abifadel M, Varret M, Rabes JP, Allard D, Ouguerram K, Devillers M, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003; 34:154-156
38. Marduel M, Carrie A, Sassolas A, Devillers M, Carreau V, Di Filippo M, et al. Molecular spectrum of autosomal dominant hypercholesterolemia in France. Hum Mutat 2010; 31:E1811-E1824
39. Abifadel M, Rabè s JP, Devillers M, Munnich A, Erlich D, Junien C, et al. Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease. Hum Mutat 2009; 30:520-529
40. Lopez D. PCSK9: an enigmatic protease. Biochim Biophys Acta 2008; 1781:184-191
41. Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006; 354:1264-1272
42. Kathiresan S. Myocardial infarction genetics C: a PCSK9 missense variant associated with a reduced risk of early-onset myocardial infarction. N Engl J Med 2008; 358:2299-2300
43. Cunningham D, Danley DE, Geoghegan KF, Griffor MC, Hawkins JL, Subashi TA, et al. Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia. Nat Struct Mol Biol 2007; 14:413-419
44. Hooper AJ, Marais AD, Tanyanyiwa DM, Burnett JR. The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population. Atherosclerosis 2007; 193:445-448
45. Zhao Z, Tuakli-Wosornu Y, Lagace TA, Kinch L, Grishin NV, Horton JD, et al. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am J Hum Genet 2006; 79:514-523
46. Denis M, Marcinkiewicz J, Zaid A, Gauthier D, Poirier S, Lazure C, et al. Gene inactivation of proprotein convertase subtilisin/kexin type 9 reduces atherosclerosis in mice. Circulation 2011; 125:894-901
47. Ferri N, Tibolla G, Pirillo A, Cipollone F, Mezzetti A, Pacia S, et al. Proprotein convertase subtilisin kexin type 9 (PCSK9) secreted by cultured smooth muscle cells reduces macrophages LDLR levels. Atherosclerosis 2012; 220:381-386
48. Tang Z, Jiang L, Peng J, Ren Z, Wei D, Wu C, et al. PCSK9 siRNA suppresses the inflammatory response induced by oxLDL through inhibition of NF-kB activation in THP-1-derived macrophages. Int J Mol Med 2012; 30:931-938
49. Roubtsova A, Munkonda MN, Awan Z, Marcinkiewicz J, Chamberland A, Lazure C, et al. Circulating proprotein convertase subtilisin/kexin 9 (PCSK9) regulates VLDLR protein and triglyceride accumulation in visceral adipose tissue. Arterioscler Thromb Vasc Biol 2011; 31:785-791
50. Desai NR, Kohli P, Giugliano RP, O'Donoghue ML, Somaratne R, Zhou J, et al. AMG145, a monoclonal antibody against proprotein convertase subtilisin kexin type 9, significantly reduces lipoprotein(a) in hypercholesterolemic patients receiving statin therapy: an analysis from the LDL-C assessment with proprotein convertase subtilisin kexin type 9 monoclonal antibody inhibition combined with statin therapy (LAPLACE)-Thrombolysis in Myocardial Infarction (TIMI) 57 trial. Circulation 2013; 128:962-969
51. Mbikay M, Sirois F, Mayne J,Wang GS, Chen A, Dewpura T, et al. PCSK9-deficient mice exhibit impaired glucose tolerance and pancreatic islet abnormalities. FEBS Lett 2010; 584:701-706
52. Brouwers MC, Troutt JS, van Greevenbroek MM, Ferreira I, Feskens EJ, van der Kallen CJ, et al. Plasma proprotein convertase subtilisin kexin type 9 is not altered in subjects with impaired glucose metabolism and type 2 diabetes mellitus, but its relationship with non-HDL cholesterol and apolipoprotein B may be modified by type 2 diabetes mellitus: the CODAM study. Atherosclerosis 2011; 217:263-267
53. Chan JC, Piper DE, Cao Q, Liu D, King C, Wang W, et al. A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates. Proc Natl Acad Sci USA 2009; 106:9820-9825
54. Foltz IN, Karow M,Wasserman SM. Evolution and emergence of therapeutic monoclonal antibodies: what cardiologists need to know. Circulation 2013; 127:2222-2230
55. Lipovsek D. Adnectins: engineered target-binding protein therapeutics. Protein Eng Des Sel 2011; 24:3-9
56. Shan L, Pang L, Zhang R, Murgolo NJ, Lan H, Hedrick JA. PCSK9 binds to multiple receptors and can be functionally inhibited by an EGF-A peptide. Biochem Biophys Res Commun 2008; 375:69-73
57. Fitzgerald K, Frank-Kamenetsky M, Shulga-Morskaya S, Liebow A, Bettencourt BR, Sutherland JE, et al. Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial. Lancet 2013; 383:60-68
58. Seidah NG. Proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors in the treatment of hypercholesterolemia and other pathologies. Curr Pharm Des 2013; 19:3161-3172
59. McKenney JM, Koren MJ, Kereiakes DJ, Hanotin C, Ferrand AC, Stein EA. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J Am Coll Cardiol 2012; 59:2344-2353
60. Roth EM, McKenney JM, Hanotin C, Asset G, Stein EA. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med 2012; 367:1891-1900
61. Stein EA, Gipe D, Bergeron J, Gaudet D,Weiss R, Dufour R, et al. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce lowdensity lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet 2012; 380:29-36
62. Koren MJ, Scott R, Kim JB, Knusel B, Liu T, Lei L, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study. Lancet 2012; 380:1995-2006
63. Sullivan D, Olsson AG, Scott R, Kim JB, Xue A, Gebski V, et al. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA 2012; 308:2497-2506
64. Raal F, Scott R, Somaratne R, Bridges I, Li G, Wasserman SM, et al. Lowdensity lipoprotein cholesterol-lowering effects of AMG145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the reduction of LDL-C with PCSK9 inhibition in heterozygous familial hypercholesterolemia disorder (RUTHERFORD) randomized trial. Circulation 2012; 126: 2408-2417
65. Giugliano RP, Desai NR, Kohli P, Rogers WJ, Somaratne R, Huang F, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study. Lancet 2012; 380:2007-2017
66. Koren MJ, Giugliano RP, Raal FJ, Sullivan D, Bolognese M, Langslet G, et al. Efficacy and safety of longer-term administration of evolocumab (AMG145) in patients with hypercholesterolemia: 52-week results from the open-label study of long-term evaluation against LDL-C (OSLER) randomized trial. Circulation 2014; 129:234-243.