Targeting the proprotein convertase subtilisin/kexin type 9 for the treatment of dyslipidemia and atherosclerosis

Journal of the American College of Cardiology

Volumn 62, Issue 16, 2013, Pages 1401-1408

  Urban, Daniel ^a   Pöss, Janine ^a   Böhm, Michael ^a   Laufs, Ulrich ^a  

^a SAARLAND UNIVERSITY   (Germany)

Author keywords

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

Indexed keywords

EID: 84885447918     PISSN: 07351097     EISSN: 15583597     Source Type: Journal    
DOI: 10.1016/j.jacc.2013.07.056     Document Type: Review

References (78)

1. N.G. Seidah, S. Benjannet, and L. Wickham The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation Proc Natl Acad Sci U S A 100 2003 928 933
2. M. Abifadel, M. Varret, and J.P. Rabès Mutations in PCSK9 cause autosomal dominant hypercholesterolemia Nat Genet 34 2003 154 156
3. K.N. Maxwell, R.E. Soccio, E.M. Duncan, E. Sehayek, and J.L. Breslow Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice J Lipid Res 44 2003 2109 2119
4. S. Benjannet, D. Rhainds, and R. Essalmani NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol J Biol Chem 279 2004 48865 48875
5. S.W. Park, Y.A. Moon, and J.D. Horton Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver J Biol Chem 279 2004 50630 50638
6. S.E. Leigh, T.P. Leren, and S.E. Humphries Commentary PCSK9 variants: A new database Atherosclerosis 203 2009 32 33
7. J. Cohen, A. Pertsemlidis, I.K. Kotowski, R. Graham, C.K. Garcia, and H.H. Hobbs Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9 Nat Genet 37 2005 161 165
8. J.C. Cohen, E. Boerwinkle, T.H. Mosley Jr., and H.H. Hobbs Sequence variations in PCSK9, low LDL, and protection against coronary heart disease N Engl J Med 354 2006 1264 1272
9. Z. Zhao, Y. Tuakli-Wosornu, and T.A. Lagace Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote Am J Hum Genet 79 2006 514 523
10. A.J. Hooper, A.D. Marais, D.M. Tanyanyiwa, and J.R. Burnett The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population Atherosclerosis 193 2007 445 448
11. N.G. Seidah, G. Mayer, and A. Zaid The activation and physiological functions of the proprotein convertases Int J Biochem Cell Biol 40 2008 1111 1125
12. N.G. Seidah, and A. Prat The biology and therapeutic targeting of the proprotein convertases Nat Rev Drug Discov 11 2012 367 383
13. G. Lambert, F. Charlton, K.A. Rye, and D.E. Piper Molecular basis of PCSK9 function Atherosclerosis 203 2009 1 7
14. N.G. Seidah, and A. Prat The proprotein convertases are potential targets in the treatment of dyslipidemia J Mol Med (Berl) 85 2007 685 696
15. E.N. Hampton, M.W. Knuth, J. Li, J.L. Harris, S.A. Lesley, and G. Spraggon The self-inhibited structure of full-length PCSK9 at 1.9 A reveals structural homology with resistin within the C-terminal domain Proc Natl Acad Sci U S A 104 2007 14604 14609
16. D.E. Piper, S. Jackson, and Q. Liu The crystal structure of PCSK9: a regulator of plasma LDL-cholesterol Structure 15 2007 545 552
17. H.J. Kwon, T.A. Lagace, M.C. McNutt, J.D. Horton, and J. Deisenhofer Molecular basis for LDL receptor recognition by PCSK9 Proc Natl Acad Sci U S A 105 2008 1820 1825
18. T.A. Lagace, D.E. Curtis, and R. Garuti Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice J Clin Invest 116 2006 2995 3005
19. D. Cunningham, D.E. Danley, and K.F. Geoghegan Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia Nat Struct Mol Biol 14 2007 413 419
20. Y.W. Qian, R.J. Schmidt, and Y. Zhang Secreted PCSK9 downregulates low density lipoprotein receptor through receptor-mediated endocytosis J Lipid Res 48 2007 1488 1498
21. J. Li, C. Tumanut, and J.A. Gavigan Secreted PCSK9 promotes LDL receptor degradation independently of proteolytic activity Biochem J 406 2007 203 207
22. P. Lo Surdo, M.J. Bottomley, and A. Calzetta Mechanistic implications for LDL receptor degradation from the PCSK9/LDLR structure at neutral pH EMBO Rep 12 2011 1300 1305
23. M.C. McNutt, T.A. Lagace, and J.D. Horton Catalytic activity is not required for secreted PCSK9 to reduce low density lipoprotein receptors in HepG2 cells J Biol Chem 282 2007 20799 20803
24. J.M. Dietschy, S.D. Turley, and D.K. Spady Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species, including humans J Lipid Res 34 1993 1637 1659
25. J.L. Goldstein, M.S. Brown, R.G. Anderson, D.W. Russell, and W.J. Schneider Receptor-mediated endocytosis: concepts emerging from the LDL receptor system Annu Rev Cell Biol 1 1985 1 39
26. J.D. Horton, N.A. Shah, and J.A. Warrington Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes Proc Natl Acad Sci U S A 100 2003 12027 12032
27. C. Le May, S. Kourimate, and C. Langhi Proprotein convertase subtilisin kexin type 9 null mice are protected from postprandial triglyceridemia Arterioscler Thromb Vasc Biol 29 2009 684 690
28. E. Levy, A.B. Ouadda, and S. Spahis PCSK9 plays a significant role in cholesterol homeostasis and lipid transport in intestinal epithelial cells Atherosclerosis 227 2013 297 306
29. J.M. McKenney, M.J. Koren, D.J. Kereiakes, C. Hanotin, A.C. Ferrand, and E.A. Stein 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 59 2012 2344 2353
30. M. Denis, J. Marcinkiewicz, and A. Zaid Gene inactivation of proprotein convertase subtilisin/kexin type 9 reduces atherosclerosis in mice Circulation 125 2012 894 901
31. N. Ferri, G. Tibolla, and A. Pirillo Proprotein convertase subtilisin kexin type 9 (PCSK9) secreted by cultured smooth muscle cells reduces macrophages LDLR levels Atherosclerosis 220 2012 381 386
32. P. Libby Inflammation in atherosclerosis Nature 420 2002 868 874
33. K.R. Feingold, A.H. Moser, J.K. Shigenaga, S.M. Patzek, and C. Grunfeld Inflammation stimulates the expression of PCSK9 Biochem Biophys Res Commun 374 2008 341 344
34. Z. Tang, L. Jiang, and J. Peng PCSK9 siRNA suppresses the inflammatory response induced by oxLDL through inhibition of NF-κB activation in THP-1-derived macrophages Int J Mol Med 30 2012 931 938
35. S. Poirier, G. Mayer, and S. Benjannet The proprotein convertase PCSK9 induces the degradation of low density lipoprotein receptor (LDLR) and its closest family members VLDLR and ApoER2 J Biol Chem 283 2008 2363 2372
36. D. Baitsch, H.H. Bock, and T. Engel Apolipoprotein E induces antiinflammatory phenotype in macrophages Arterioscler Thromb Vasc Biol 31 2011 1160 1168
37. K. Kysenius, P. Muggalla, K. Mätlik, U. Arumäe, and H.J. Huttunen PCSK9 regulates neuronal apoptosis by adjusting ApoER2 levels and signaling Cell Mol Life Sci 69 2012 1903 1916
38. T. Ranheim, M. Mattingsdal, and J.M. Lindvall Genome-wide expression analysis of cells expressing gain of function mutant D374Y-PCSK9 J Cell Physiol 217 2008 459 467
39. C.Y. Wu, Z.H. Tang, L. Jiang, X.F. Li, Z.S. Jiang, and L.S. Liu PCSK9 siRNA inhibits HUVEC apoptosis induced by ox-LDL via Bcl/Bax-caspase9-caspase3 pathway Mol Cell Biochem 359 2012 347 358
40. E. Rousselet, J. Marcinkiewicz, and J. Kriz PCSK9 reduces the protein levels of the LDL receptor in mouse brain during development and after ischemic stroke J Lipid Res 52 2011 1383 1391
41. V. Sharotri, D.M. Collier, D.R. Olson, R. Zhou, and P.M. Snyder Regulation of epithelial sodium channel trafficking by proprotein convertase subtilisin/kexin type 9 (PCSK9) J Biol Chem 287 2012 19266 19274
42. J.A. Beckman, M.A. Creager, and P. Libby Diabetes and atherosclerosis: epidemiology, pathophysiology, and management JAMA 287 2002 2570 2581
43. M. Mbikay, F. Sirois, and J. Mayne PCSK9-deficient mice exhibit impaired glucose tolerance and pancreatic islet abnormalities FEBS Lett 584 2010 701 706
44. G. Fantuzzi, and T. Mazzone Adipose tissue and atherosclerosis: exploring the connection Arterioscler Thromb Vasc Biol 27 2007 996 1003
45. A. Roubtsova, M.N. Munkonda, and Z. Awan Circulating proprotein convertase subtilisin/kexin 9 (PCSK9) regulates VLDLR protein and triglyceride accumulation in visceral adipose tissue Arterioscler Thromb Vasc Biol 31 2011 785 791
46. S. Yusuf, S. Hawken, and S. Ounpuu Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study Lancet 364 2004 937 952
47. C. Baigent, A. Keech, and P.M. Kearney Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins Lancet 366 2005 1267 1278
48. T.A. Pearson, I. Laurora, H. Chu, and S. Kafonek The lipid treatment assessment project (L-TAP): a multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving low-density lipoprotein cholesterol goals Arch Intern Med 160 2000 459 467
49. C.A. Sueta, M. Chowdhury, and S.J. Boccuzzi Analysis of the degree of undertreatment of hyperlipidemia and congestive heart failure secondary to coronary artery disease Am J Cardiol 83 1999 1303 1307
50. A.K. Gitt, H. Drexel, and J. Feely Persistent lipid abnormalities in statin-treated patients and predictors of LDL-cholesterol goal achievement in clinical practice in Europe and Canada Eur J Prev Cardiol 19 2012 221 230
51. U. Laufs, W.S. Weintraub, and C.J. Packard Beyond statins: what to expect from add-on lipid regulating therapy? Eur Heart J 2013 [E-pub ahead of print]
52. H.E. Careskey, R.A. Davis, W.E. Alborn, J.S. Troutt, G. Cao, and R.J. Konrad Atorvastatin increases human serum levels of proprotein convertase subtilisin/kexin type 9 J Lipid Res 49 2008 394 398
53. G. Welder, I. Zineh, M.A. Pacanowski, J.S. Troutt, G. Cao, and R.J. Konrad High-dose atorvastatin causes a rapid sustained increase in human serum PCSK9 and disrupts its correlation with LDL cholesterol J Lipid Res 51 2010 2714 2771
54. Z. Awan, N.G. Seidah, and J.G. MacFadyen Rosuvastatin, proprotein convertase subtilisin/kexin type 9 concentrations, and LDL cholesterol response: the JUPITER trial Clin Chem 58 2012 183 189
55. H.J. Jeong, H.S. Lee, K.S. Kim, Y.K. Kim, D. Yoon, and S.W. Park Sterol-dependent regulation of proprotein convertase subtilisin/kexin type 9 expression by sterol-regulatory element binding protein-2 J Lipid Res 49 2008 399 409
56. K.E. Berge, L. Ose, and T.P. Leren Missense mutations in the PCSK9 gene are associated with hypocholesterolemia and possibly increased response to statin therapy Arterioscler Thromb Vasc Biol 26 2006 1094 1100
57. J.F. Thompson, C.L. Hyde, and L.S. Wood Comprehensive whole-genome and candidate gene analysis for response to statin therapy in the treating to new targets (TNT) cohort Circ Cardiovasc Genet 2 2009 173 181
58. L. Shan, L. Pang, R. Zhang, N.J. Murgolo, H. Lan, and J.A. Hedrick PCSK9 binds to multiple receptors and can be functionally inhibited by an EGF-A peptide Biochem Biophys Res Commun 375 2008 69 73
59. F. Du, Y. Hui, M. Zhang, M.F. Linton, S. Fazio, and D. Fan Novel domain interaction regulates secretion of proprotein convertase subtilisin/kexin type 9 (PCSK9) protein J Biol Chem 286 2011 43054 43061
60. D. Lipovsek Adnectins: engineered target-binding protein therapeutics Protein Eng Des Sel 24 2011 3 9
61. S. Benjannet, J. Hamelin, M. Chrétien, and N.G. Seidah Loss- and gain-of-function PCSK9 variants: cleavage specificity, dominant negative effects, and low density lipoprotein receptor (LDLR) degradation J Biol Chem 287 2012 33745 33755
62. R.Q. Do, R.A. Vogel, and G.G. Schwartz PCSK9 Inhibitors: potential in cardiovascular therapeutics Curr Cardiol Rep 15 2013 345
63. M.J. Graham, K.M. Lemonidis, and C.P. Whipple Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice J Lipid Res 48 2007 763 767
64. N. Gupta, N. Fisker, and M.C. Asselin A locked nucleic acid antisense oligonucleotide (LNA) silences PCSK9 and enhances LDLR expression in vitro and in vivo PLoS One 5 2010 e10682
65. M.W. Lindholm, J. Elmén, and N. Fisker PCSK9 LNA antisense oligonucleotides induce sustained reduction of LDL cholesterol in nonhuman primates Mol Ther 20 2012 376 381
66. M. Frank-Kamenetsky, A. Grefhorst, and N.N. Anderson Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates Proc Natl Acad Sci U S A 105 2008 11915 11920
67. Alnylam Pharmaceuticals. Alnylam 5x15 Programs: Hypercholestoralemia. Available at: http://www.alnylam.com/Programs-and-Pipeline/Alnylam-5x15/ Hypercholestoralemia.php. Accessed July 16, 2013.
68. J.C. Chan, D.E. Piper, and Q. Cao A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates Proc Natl Acad Sci U S A 106 2009 9820 9825
69. C.S. Dias, A.J. Shaywitz, and S.M. Wasserman Effects of AMG 145 on low-density lipoprotein cholesterol levels: results from 2 randomized, double-blind, placebo-controlled, ascending-dose phase 1 studies in healthy volunteers and hypercholesterolemic subjects on statins J Am Coll Cardiol 60 2012 1888 1898
70. D. Sullivan, A.G. Olsson, and R. Scott Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial JAMA 308 2012 2497 2506
71. F. Raal, R. Scott, and R. Somaratne Low-density lipoprotein cholesterol-lowering effects of AMG 145, 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 126 2012 2408 2417
72. R.P. Giugliano, N.R. Desai, and P. Kohli 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 380 2012 2007 2017
73. M.J. Koren, R. Scott, and J.B. Kim 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 380 2012 1995 2006
74. E.A. Stein, and G.D. Swergold Potential of proprotein convertase subtilisin/kexin type 9 based therapeutics Curr Atheroscler Rep 15 2013 310
75. U.S. National Institutes of Health. Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER). Available at: http://clinicaltrials.gov/ct2/show/NCT01764633. Accessed July 16, 2013.
76. E.A. Stein, S. Mellis, and G.D. Yancopoulos Effect of a monoclonal antibody to PCSK9 on LDL cholesterol N Engl J Med 366 2012 1108 1118
77. E.A. Stein, D. Gipe, and J. Bergeron Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial Lancet 380 2012 29 36
78. E.M. Roth, J.M. McKenney, C. Hanotin, G. Asset, and E.A. Stein Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia N Engl J Med 367 2012 1891 1900