Proprotein convertase subtilisin kexin9 (pcsk9): A novel target for cholesterol regulation

Protein and Peptide Letters

Volumn 19, Issue 6, 2012, Pages 575-585

  Basak, Ajoy ^a,b   Palmer Smith, Heather ^a   Mishra, Priyambada ^a  

^a OTTAWA HOSPITAL RESEARCH INSTITUTE   (Canada)

^b UNIVERSITY OF OTTAWA   (Canada)

Author keywords

Cholesterol lowering agents; Hypercholesterolemia; Low density lipoprotein receptor; Low density lipoproteincholesterol; PCSK9 inhibitors; Proprotein convertase subtilisin Kexin9 (PCSK9)

Indexed keywords

41 MER SYNTHETIC EGF A PEPTIDE; ANTISENSE OLIGONUCLEOTIDE; CHOLESTEROL; COMPLEMENTARY DNA; CYTOKINE ONCHOSTATIN M; ENZYME INHIBITOR; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; HYPOCHOLESTEROLEMIC AGENT; LOW DENSITY LIPOPROTEIN RECEPTOR; MONOCLONAL ANTIBODY; NEURAL APOPTOSIS REGULATED CONVERTASE 1; PEPTIDE; POLYCLONAL ANTIBODY; PROPROTEIN CONVERTASE SUBTILISIN KEXIN9; PROPROTEIN CONVERTASE SUBTILISIN KEXIN9 INHIBITOR; SERINE PROTEINASE; SUBTILISIN; UNCLASSIFIED DRUG; WO 143315;

ARTICLE; CARDIOVASCULAR DISEASE; CHOLESTEROL BLOOD LEVEL; CHOLESTEROL REGULATION; DRUG TARGETING; ENZYME ACTIVITY; ENZYME INHIBITION; GAIN OF FUNCTION MUTATION; HUMAN; HYPERCHOLESTEROLEMIA; LOSS OF FUNCTION MUTATION; NONHUMAN; PATENT; PROTEIN DEGRADATION; REGULATORY MECHANISM; RISK FACTOR; TRANSGENIC ANIMAL; UNSPECIFIED SIDE EFFECT;

ANIMALIA; MAMMALIA;

EID: 84861921405     PISSN: 09298665     EISSN: None     Source Type: Journal    
DOI: 10.2174/092986612800494020     Document Type: Article

References (80)

1. Davidson, M. H. Novel nonstatin strategies to lower low-density lipoprotein cholesterol. Curr. Atheroscler. Rep., 2009, 11, 67-70.
2. Austin, M. A.; Hutter, C. M.; Zimmern, R. L.; Humphries, S. E. Familial hypercholesterolemia and coronary heart disease: a HuGE association review. Am. J. Epidemiol., 2004, 160(5), 421-429. (Pubitemid 39166974)
3. Civeira, F. Guidelines for the diagnosis and management of heterozygous familial hypercholesterolemia. Atherosclerosis, 2004, 173(1), 55-68. (Pubitemid 38224196)
4. Briel, M.; Nordmann, A.J.; Bucher, H. C. Statin therapy for prevention and treatment of acute and chronic cardiovascular disease: update on recent trials and metaanalyses. Curr. Opin. Lipidol., 2005, 16, 601-605. (Pubitemid 43012155)
5. Steinberg, D.; Witztum, J. L. Inhibition of PCSK9: a powerful weapon for achieving ideal LDL cholesterol levels. Proc. Natl. Acad. Sci. USA, 2009, 106(24), 9546-9547.
6. Tardif, J. C.; Grégoire, J.; L'Allier, P. L.; Anderson, T. J.; Bertrand, O.; Reeves, F.; Title, L. M.; Alfonso, F.; Schampaert, E.; Hassan, A.; McLain, R.; Pressler, M. L.; Ibrahim, R.; Lespérance, J.; Blue, J.; Heinonen, T.; Rodés-Cabau, J. Effects of the acyl coenzyme A: cholesterol acyltransferase inhibitor avasimibe on human atherosclerotic lesions. Circulation, 2004, 110(21), 3372-3377. (Pubitemid 39557502)
7. Nissen, S. E.; Tuzcu, E. M.; Brewer, H. B.; Sipahi, I.; Nicholls, S. J.; Ganz, P.; Schoenhagen, P.; Waters, D. D.; Pepine, C. J.; Crowe, T. D.; Davidson, M. H.; Deanfield, J. E.; Wisniewski, L. M.; Hanyok, J. J.; Kassalow, L. M. Effect of ACAT inhibition on the progression of coronary atherosclerosis. N. Engl. J Med., 2006, 354, 1253-1263.
8. Chandler, C. E.; Wilder, D. E.; Pettini, J. L.; Savoy, Y. E.; Petras, S. F.; Chang, G.; Vincent, J.; Harwood, H. J. Jr. CP-346086: an MTP inhibitor that lowers plasma cholesterol and triglycerides in experimental animals and in humans. J. Lipid Res., 2003, 44, 1887-1901. (Pubitemid 37356661)
9. Kim, E.; Campbell, S.; Schueller, O.; Wong, E.; Cole, B.; Kuo, J.; Ferkany, J.; Ellis, J.; Sweetnam, P. J. A small-molecule inhibitor of enterocytic microsomal triglyceride transfer protein, SLx-4090: biochemical, pharmacodynamic, pharmacokinetic, and safety profile. Pharmacol. Exp. Ther., 2011, 337 (3), 775-785.
10. Nishimoto, T.; Amano, Y.; Tozawa, R.; Ishikawa, E.; Imura, Y.; Yukimasa, H.; Sugiyama, Y. Lipid-lowering properties of TAK-475, a squalene synthase inhibitor, in vivo and in vitro. Br. J. Pharmacol., 2003, 139, 911-918. (Pubitemid 36877390)
11. Brown, M. S.; Goldstein, J. L. Biomedicine. Lowering LDL-not only how low, but how long? Science, 2006, 311, 1721-1723.
12. Seidah, N. G.; Benjannet, S.; Wickham, L.; Marcinkiewicz, J.; Jasmin, S. B.; Stifani, S.; Basak, A.; Prat, A.; Chretien M. Biomedicine. The secretory proprotein convertase neural apoptosisregulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc. Natl. Acad. Sci. USA, 2003, 100, 928-936.
13. Grefhorst, A.; McNutt, M. C.; Lagace, T. A.; Horton, J. D. Plasma PCSK9 preferentially reduces liver LDL receptors in mice. J. Lipid Res., 2008, 49, 1303-1311.
14. Maxwell, K. N.; Fisher, E. A.; Breslow, J. L. Overexpression of PCSK9 accelerates the degradation of the LDLR in a postendoplasmic reticulum compartment. Proc. Natl. Acad. Sci. USA, 2005, 102(6), 2069-2074. (Pubitemid 40262013)
15. Kathiresan, S. A. PCSK9 missense variant associated with a reduced risk of early-onset myocardial infarction. N. Engl. J. Med., 2008, 358(21), 2299-2300.
16. Lan, H.; Pang, L.; Smith, M. M.; Levitan, D.; Ding, W.; Liu, L.; Shan, L.; Shah, V. V.; Laverty, M.; Arreaza, G.; Zhang, Q.; Murgolo, N. J.; Hernande, M.; Greene, J. R.; Gustafson, E. L.; Bayne, M. L.; Davis, H. R.; Hedrick, J. A. Proprotein convertase subtilisin/kexin type 9 (PCSK9) affects gene expression pathways beyond cholesterol metabolism in liver cells. J. Cell Physiol., 2010, 224(1), 273-281.
17. Li, H.; Li, H.; Ziegler, N.; Cui, R.; Liu, J. Recent patents on PCSK9: a new target for treating hypercholesterolemia. Recent Pat. DNA Gene Seq., 2009, 3(3), 201-212
18. Seidah, N. G. PCSK9 as a therapeutic target of dyslipidemia. Expert Opin. Ther. Targets, 2009, 13(1), 19-28.
19. Lopez, D. Inhibition of PCSK9 as a novel strategy for the treatment of hypercholesterolemia. Drug News Perspect., 2008, 21(6), 323-330.
20. Horton, J. D.; Cohen, J. C.; Hobbs, H. H. PCSK9: a convertase that coordinates LDL catabolism. J. Lipid Res., 2009, 50 Suppl: S172-177.
21. Lilly, S. M.; Rader, D. J. New targets and emerging therapies for reducing LDL cholesterol, Curr. Opin. Lipidol., 2007, 18, 650-655. (Pubitemid 350098570)
22. Costet, P.; Krempf, M.; Cariou, B. PCSK9 and LDL cholesterol: unravelling the target to design the bullet. Trends Biochem. Sci., 2008, 33, 426-434.
23. Maxwell, K. N.; Breslow, J. L. Proprotein convertase subtilisin kexin 9: the third locus implicated in autosomal dominant hypercholesterolemia. Curr. Opin. Lipidol., 2005, 16(2), 167-172. (Pubitemid 40515890)
24. Lambert, G.; Charlton, F.; Rye K. A.; Piper, D. E. Molecular basis of PCSK9 function. Atherosclerosis, 2009, 203(1), 1-7.
25. Mousavi, S. A.; Berge, K. E.; Leren, T. P. The unique role of proprotein convertase subtilisin/kexin 9 in cholesterol homeostasis. J. Intern. Med., 2009, 266(6), 507-519.
26. Varret, M.; Abifadel, M.; Rabès, J. P.; Boileau, C. Genetic heterogeneity of autosomal dominant hypercholesterolemia. Clin. Genet., 2008, 73(1), 1-13. (Pubitemid 350263516)
27. McNutt, M. C.; Lagace, T. A.; Horton, J. D. Catalytic activity is not required for secreted PCSK9 to reduce low density lipoprotein receptors in HepG2 cells. J. Biol. Chem., 2007, 282(29), 20799-20803. (Pubitemid 47099894)
28. Jeon, H.; Blacklow, S. C. Structure and physiologic function of the low-density lipoprotein receptor. Annu. Rev. Biochem., 2005, 74, 535-562. (Pubitemid 40995517)
29. Zhang. J.; Herscovitz, H. Nascent lipidated apolipoprotein B is transported to the Golgi as an incompletely folded intermediate as probed by its association with network of endoplasmic reticulum molecular chaperones, GRP94, ERp72, BiP, calreticulin, and cyclophilin B. J. Biol. Chem., 2003, 278(9), 7459-7468. (Pubitemid 36800752)
30. García-Otín, A. L.; Cofán, M.; Junyent, M.; Recalde, D.; Cenarro, A.; Pocoví, M.; Ros, E.; Civeira, F. Increased intestinal cholesterol absorption in autosomal dominant hypercholesterolemia and no mutations in the low-density lipoprotein receptor or apolipoprotein B genes. J. Clin. Endocrinol. Metab., 2007, 92(9), 3667-3673. (Pubitemid 47435354)
31. Marques-Pinheiro, A. ; Marduel, M. ; Rabès, J. P. ; Devillers, M. ; Villéger, L. ; Allard, D. ; Weissenbach, J. ; Guerin, M.; Zair, Y.; Erlich, D.; Junien, C.; Munnich, A.; Krempf, M.; Abifadel M.; Jaïs, J. P. A fourth locus for autosomal dominant hypercholesterolemia maps at 16q22.1. Eur. J. Hum. Genet., 2010, 18(11), 1236-1242.
32. Benjannet, S.; Rhainds, D.; Essalmani, R.; Mayne, J.; Wickham, L.; Jin, W.; Asselin, M. C.; Hamelin, J.; Varret, M.; Allard, D.; Trillard, M.; Abifadel, M.; Tebon, A.; Attie, A. D.; Rader, D. J.; Boileau, C.; Brissette, L.; Chrétien, M.; Prat, A.; Seidah, N. G. NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol. J. Biol. Chem., 2004, 279(47), 48865-48875. (Pubitemid 39625767)
33. Kourimate, S.; Chetiveaux, M.; Jarnoux, A. L.; Lalanne, F.; Costet, P. Cellular and secreted pro-protein convertase subtilisin/kexin type 9 catalytic activity in hepatocytes. Atherosclerosis, 2009, 206(1), 134-140.
34. Grozdanov, P. N.; Petkov, P. M.; Karagyozov, L. K.; Dabeva, M. D. Expression and localization of PCSK9 in rat hepatic cells. Biochem. Cell. Biol., 2006, 84, 80-92.
35. Luo, Y.; Warren, L.; Xia, D.; Jensen, H.; Sand, T.; Petras, S.; Qin, W.; Miller, K. S.; Hawkins Function and distribution of circulating human PCSK9 expressed extrahepatically in transgenic mice. J. Lipid Res., 2009, 50(8), 1581-1588.
36. Cunningham, D.; Danley, D. E.; Geoghegan, K. F.; Griffor, M. C.; Hawkins, J. L.; Subashi, T. A.; Varghese, A. H.; Ammirati, M. J.; Culp, J. S.; Hoth, L. R.; Mansour, M. N.; McGrath, K. M.; Seddon, A.P.; Shenolikar, S.; Stutzman-Engwall, K. J.; Warren, L. C.; Xia, D.; Qiu, X. Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia. Nat. Struct. Mol. Biol., 2007, 14, 413-419. (Pubitemid 46685885)
37. Piper, D.E.; Jackson, S.; Liu, Q.; Romanow, W. G.; Shetterly, S.; Thibault, S. T.; Shan, B.; Walker, N. P. The crystal structure of PCSK9: a regulator of plasma LDL-cholesterol. Structure, 2007, 15(5), 545-552. (Pubitemid 46702689)
38. Kwon, H. J.; Lagace, T. A.; McNutt, M. C.; Horton, J. D.; Deisenhofer, J. Molecular basis for LDL receptor recognition by PCSK9. Proc. Natl. Acad. Sci. USA, 2008, 105, 1820-1825. (Pubitemid 351439423)
39. Schmidt, R. J.; Schmidt, R. J.; Beyer, T. P.; Bensch, W. R.; Qian, Y. W.; Lin, A.; Kowala, M.; Alborn, W. E.; Konrad, R. J.; Cao, G. Secreted proprotein convertase subtilisin/kexin type 9 reduces both hepatic and extrahepatic low-density lipoprotein receptors in vivo. Biochem. Biophys. Res. Commun., 2008, 370(4), 634-640.
40. Lagace, T. A.; Curtis, D.E.; Garuti, R.; McNutt, M. C.; Park, S. W.; Prather, H. B.; Anderson, N. N.; Ho, Y. K.; Hammer, R. E.; Horton, J. D. Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice. J. Clin. Invest., 2006, 116, 2995-3005. (Pubitemid 44684484)
41. Cameron, J. J.; Holla, Ø. L.; Ranheim, T.; Kulseth, M. A.; Berge, K. E.; Leren, T. P. Effect of mutations in the PCSK9 gene on the cell surface LDL receptors. Hum. Mol. Genet., 2006, 15, 1551-1558.
42. Poirier, S.; Mayer, G.; Benjannet, S.; Bergeron, E.; Marcinkiewicz, J.; Nassoury, N.; Mayer, H.; Nimpf, J.; Prat, A.; Seidah, N. G. The proprotein convertase PCSK9 induces the degradation of low density lipoprotein receptor (LDLR) and its closest family members VLDLR and ApoER2. J. Biol. Chem., 2008, 283, 2363-2372.
43. Benjannet, S.; Rhainds, D.; Hamelin, J.; Nassoury, N.; Seidah, N. G. The proprotein convertase (PC) PCSK9 is inactivated by furin and/or PC5/6A: functional consequences of natural mutations and post-translational modifications. J. Biol. Chem., 2006, 281, 30561-30572. (Pubitemid 44582112)
44. Benjannet, S.; Saavedra, Y. G.; Hamelin, J.; Asselin, M. C.; Essalmani, R.; Pasquato, A.; Lemaire, P.; Duke, G.; Miao, B.; Duclos, F.; Parker, R.; Mayer, G.; Seidah, N. G. Effects of the prosegment and pH on the activity of PCSK9: evidence for additional processing events. J. Biol. Chem., 2010, 285(52), 40965-40978.
45. Cohen, J. D.; Hobbs, H. H. Molecular biology of PCSK9: its role in LDL metabolism. Trends Biochem. Sci., 2007, 32(2), 71-77. (Pubitemid 46199197)
46. Dewpura, T.; Raymond, A.; Hamelin, J.; Seidah, N. G.; Mbikay, M.; Chrétien. M.; Mayne J. PCSK9 is phosphorylated by a Golgi casein kinase-like kinase ex vivo and circulates as a phosphoprotein in humans. FEBS J., 2008, 275, 3480-3493. (Pubitemid 351813558)
47. Lambert, G. Unravelling the functional significance of PCSK9. Curr. Opin. Lipidol., 2007, 18, 304-309. (Pubitemid 46743055)
48. Fan, D.; Yancey, P. G.; Qiu, S.; Ding, L.; Weeber, E. J.; Linton, M. F.; Fazio, S. Self-association of human PCSK9 correlates with its LDLR-degrading activity. Biochemistry, 2008, 47, 1631-1639. (Pubitemid 351231213)
49. Abifadel, M.; Rabes, J. P.; Boileau, C.; Varret, M. After the LDL receptor and apolipoprotein B, autosomal dominant hypercholesterolemia reveals its third protagonist: PCSK9 Ann. Endocrinol. (Paris), 2007, 68(2-3), 138-146. (Pubitemid 47241113)
50. Zhang, D. W.; Lagace, T. A.; Garuti, R.; Zhao, Z.; McDonald, M.; Horton, J. D.; Cohen, J. C.; Hobbs, H. H. Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation. J. Biol. Chem., 2007, 282(25), 18602-18612. (Pubitemid 47100234)
51. Zhang, D. W.; Garuti, R.; Tang, W. J.; Cohen, J. C.; Hobbs, H. H. Structural requirements for PCSK9-mediated degradation of the low-density lipoprotein receptor. Proc. Natl. Acad. Sci. USA, 2008, 105(35), 13045-13050.
52. Mayer, G.; Poirier, S.; Seidah, N. G. Annexin A2 is a C-terminal PCSK9-binding protein that regulates endogenous low density lipoprotein receptor levels. J. Biol. Chem., 2008, 283(46), 31791-31801.
53. Naureckiene, S.; Ma, L.; Sreekumar, K.; Purandare, U.; Lo, C. F.; Huang, Y.; Chiang, L. W.; Grenier, J. M.; Ozenberger B. A.; Jacobsen, J. S.; Kennedy, J. D.; DiStefano, P. S.; Wood, A.; Bingham, B. Functional characterization of Narc 1, a novel proteinase related to proteinase K. Arch. Biochem. Biophys., 2003, 420(1), 55-67. (Pubitemid 37393374)
54. Pearlstein, R. A.; Hu, Q. Y.; Zhou, J.; Yowe, D.; Levell, J.; Dale, B.; Kaushik, V. K.; Daniels, D.; Hanrahan, S.; Sherman, W.; Abel, R. New hypotheses about the structure-function of proprotein convertase subtilisin/kexin type 9: analysis of the epidermal growth factor-like repeat A docking site using WaterMap. Proteins, 2010, 78(12), 2571-2586.
55. Abifadel, M.; Pakradouni, J.; Collin, M.; Samson-Bouma, M. E.; Varret, M.; Rabès, J. P.; Boileau, C. Strategies for proprotein convertase subtilisin kexin 9 modulation: a perspective on recent patents. Expert. Opin. Ther. Pat., 2010, 20(11), 1547-1571.
56. Ni, Y. G.; Di Marco, S.; Condra, J. H.; Peterson, L. B.; Wang, W.; Wang, F.; Pandit, S.; Hammond, H. A.; Rosa, R.; Cummings, R. T.; Wood, D. D.; Liu, X.; Bottomley, M. J.; Shen, X.; Cubbon, R. M.; Wang, S. P.; Johns, D. G.; Volpari, C.; Hamuro, L.; Chin, J.; Huang, L.; Zhao, J. Z.; Vitelli, S.; Haytko, P.; Wisniewski, D.; Mitnaul, L. J.; Sparrow, C.P.; Hubbard, B.; Carfí, A.; Sitlani, A. A PCSK9-binding antibody that structurally mimics the EGF(A) domain of LDL-receptor reduces LDL cholesterol in vivo. J. Lipid Res., 2011, 52(1), 78-86.
57. Palmer-Smith, H.; Basak, A. Regulatory effects of peptides from the pro and catalytic domains of proprotein convertase subtilisin/ kexin 9 PCSK9 on low-density lipoprotein receptor (LDL-R). Curr. Med. Chem., 2010, 17, 2168-2182.
58. Cariou, B.; Le Bras, M.; Langhi, C.; Le May, C.; Guyomarc'h-Delasalle, B.; Krempf, M.; Costet, P. Association between plasma PCSK9 and gamma-glutamyl transferase levels in diabetic patients. Atherosclerosis, 2010, 11(2), 700-702.
59. Denis, N.; Palmer-Smith, H.; Elisma, F.; Busuttil, A.; Wright, T. G,; Khalil, M. B.; Prat, A.; Seidah, N. G.; Chretien, M.; Mayne, J.; Figeys, D. Quantitative proteomic analysis of PCSK9 gain of function in human hepatic HuH7 cells. J. Proteome Res., 2011, 10(4), 2011-2026.
60. Bottomley, M. J.; Cirillo, A.; Orsatti, L.; Ruggeri, L.; Fisher, T. S.; Santoro, J. C.; Cummings, R. T.; Cubbon, R. M.; Lo Surdo, P.; Calzetta, A.; Noto, A.; Baysarowich, J.; Mattu, M.; Talamo, F.; De Francesco, R.; Sparrow, C. P.; Sitlani, A.; Carfí, A. Structural and biochemical characterization of the wild type PCSK9-EGF(AB) complex and natural familial hypercholesterolemia mutants. J. Biol. Chem., 2009, 284(2), 1313-1323.
61. Yamamoto, T.; Lu, C.; Ryan, R. O. A two-step binding model of PCSK9 interaction with the low density lipoprotein receptor. J. Biol. Chem., 2011, 286(7), 5464-5470.
62. Soutar, A. K. Unexpected roles for PCSK9 in lipid metabolism. Curr. Opin. Lipidol., 2011, 22(3), 192-196.
63. Zaid, A.; Roubtsova, A.; Essalmani, R.; Marcinkiewicz, J.; Chamberland, A.; Hamelin, J.; Tremblay, M.; Jacques, H.; Jin, W.; Davignon, J.; Seidah, N. G.; Prat, A. Proprotein convertase subtilisin/ kexin type 9 (PCSK9): hepatocyte-specific low-density lipoprotein receptor degradation and critical role in mouse liver regeneration. Hepatology, 2008, 48(2), 646-654.
64. Creemers, J. W.; Khatib, A-M. Knock-out mouse models of proprotein convertases: unique functions or redundancy? Front. Biosci., 2008, 13, 4960-4971. (Pubitemid 351599650)
65. O'Rahilly. S.; Gray, H.; Humphreys, P. J.; Krook, A.; Polonsky, K. S.; White, A.; Gibson, S.; Taylor, K.; Carr, C. Brief report: impaired processing of prohormones associated with abnormalities of glucose homeostasis and adrenal function. N. Engl. J. Med., 1995, 333, 1386-1390.
66. Jackson, R. S.; Creemers, J. W.; Ohagi, S.; Raffin-Sanson, M. L.; Sanders, L.; Montague, C. T.; Hutton, J. C.; O'Rahilly, S. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat. Gene., 1997, 16, 303-306. (Pubitemid 27280217)
67. Mbikay, M.; Sirois, F.; Nkongolo, K. K.; Basak, A.; Chrétien, M. Effects of rs6234/rs6235 and rs6232/rs6234/rs6235 PCSK1 singlenucleotide polymorphism clusters on proprotein convertase 1/3 biosynthesis and activity. Mol. Genet. Metab., 2011, 104(4), 682-687.
68. Strøm, T. B.; Holla, Ø. L.; Cameron, J.; Berge, K. E.; Leren, T. P. Loss-of-function mutation R46L in the PCSK9 gene has little impact on the levels of total serum cholesterol in familial hypercholesterolemia heterozygotes. Clin. Chim. Acta, 2010, 411, 229-233.
69. Mayne J, Dewpura T, Raymond A, Bernier L, Cousins M, Ooi TC, Davignon J, Seidah NG, Mbikay M, Chrétien M. Novel loss-of function PCSK9 variant is associated with low plasma LDL cholesterol in a French-Canadian family and with impaired processing and secretion in cell culture. Clin. Chem., 2011, 57(10), 1415-1423.
70. Jelassi, A.; Slimani, A.; Jguirim, I.; Najah, M.; Maatouk, F.; Varret, M.; Slimane, M. N. Effect of a splice site mutation in LDLR gene and two variations in PCSK9 gene in Tunisian families with familial hypercholesterolaemia. Ann. Clin. Biochem., 2011, 48(Pt 1), 83-86.
71. Mayne, J.; Dewpura, T.; Raymond, A.; Cousins, M.; Chaplin, A.; Lahey, K. A.; Haye, S. A.; Mbikay, M.; Ooi, T. C.; Chrétien, M. Plasma PCSK9 levels are significantly modified by statins and fibrates in humans. Lipids Health Dis., 2008, 7, 22-31.
72. Cohen, J. C.; Boerwinkle, E.; Mosley, T. H. Jr.; Hobbs, H. H. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N. Engl. J. Med. 2006, 354(12), 1264-1272.
73. Gouni-Berthold, I.; Berthold, H. K. Antisense oligonucleotides for the treatment of dyslipidemia. Curr. Pharm. Des., 2011, 17(9), 950-960.
74. Graham, M. J.; Lemonidis, K. M.; Whipple, C. P.; Subramaniam, A.; Monia, B. P.; Crooke, S. T.; Crooke, R. M. Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice. J. Lipid Res., 2007, 48(4), 763-767. (Pubitemid 46557881)
75. Gupta, N.; Fisker, N.; Asselin, M. C.; Lindholm, M.; Rosenbohm, C.; Ørum, H.; Elmén, J.; Seidah, N. G.; Straarup, E. M. A locked nucleic acid antisense oligonucleotide (LNA) silences PCSK9 and enhances LDLR expression in vitro and in vivo. PLoS One, 2010, 5(5), e10682.
76. Le Gall, S.; Neuhof, A.; Rapoport, T. The endoplasmic reticulum membrane is permeable to small molecules. Mol. Biol. Cell, 2004, 15, 447-455. (Pubitemid 38146464)
77. Chan, J. C.; Piper, D. E.; Cao, Q.; Liu, D.; King, C.; Wang, W.; Tang, J.; Liu, Q.; Higbee, J.; Xia, Z.; Di, Y.; Shetterly, S.; Arimura, Z.; Salomonis, H.; Romanow, W. G.; Thibault, S. T.; Zhang, R.; Cao, P.; Yang, X. P.; Yu, T.; Lu, M.; Retter, M. W.; Kwon, G.; Henne, K.; Pan, O.; Tsai, M. M.; Fuchslocher, B.; Yang, E.; Zhou, L.; Lee, K. J.; Daris, M.; Sheng, J.; Wang, Y.; Shen, W. D.; Yeh, W. C.; Emery, M.; Walker, N. P.; Shan, B.; Schwarz, M.; Jackson, S. M. 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.
78. Fu, T-M.; Mylin, L. M.; Schell, T. D.; Bacik, I.; Russ, G.; Yewdell, J. W.; Bennink, J. R.; Tevethia, S. S. An endoplasmic reticulumtargeting signal sequence enhances the immunogenicity of an immunorecessive simian virus 40 large T antigen cytotoxic Tlymphocyte epitope. J. Virol., 1998, 72, 1469-1481. (Pubitemid 28116935)
79. Labonté, P.; Begley, S.; Guévin, C.; Asselin, M. C.; Nassoury, N.; Mayer, G.; Prat, A.; Seidah, N. G. PCSK9 impedes hepatitis C virus infection in vitro and modulates liver CD81 expression. Hepatology, 2009, 50(1), 17-24.
80. Benn, M.; Tybjærg-Hansen, A.; Stender, S.; Frikke-Schmidt, R.; Nordestgaard, B. G. Low-density lipoprotein cholesterol and the risk of cancer: a mendelian randomization study. J. Natl. Cancer Inst., 2011, 103(6), 508-519.