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Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition: A New Therapeutic Mechanism for Reducing Cardiovascular Disease Risk

Bergeron, Nathalie, Phan, Binh An P., Ding, Yunchen, Fong, Aleyna, Krauss, Ronald M.·2015·Circulation
DOI 10.1161/circulationaha.115.016080
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Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in the regulation of cholesterol homeostasis. By binding to hepatic low-density lipoprotein (LDL) receptors and promoting their lysosomal degradation, PCSK9 reduces LDL uptake, leading to an increase in LDL cholesterol concentrations. Gain-of-function mutations in PCSK9 associated with high LDL cholesterol and premature cardiovascular disease have been causally implicated in the pathophysiology of autosomal-dominant familial hypercholesterolemia. In contrast, the more commonly expressed loss-of-function mutations in PCSK9 are associated with reduced LDL cholesterol and cardiovascular disease risk. The development of therapeutic approaches that inhibit PCSK9 function has therefore attracted considerable attention from clinicians and the pharmaceutical industry for the management of hypercholesterolemia and its associated cardiovascular disease risk. This review summarizes the effects of PCSK9 on hepatic and intestinal lipid metabolism and the more recently explored functions of PCSK9 in extrahepatic tissues. Therapeutic approaches that prevent interaction of PCSK9 with hepatic LDL receptors (monoclonal antibodies, mimetic peptides), inhibit PCSK9 synthesis in the endoplasmic reticulum (antisense oligonucleotides, siRNAs), and interfere with PCSK9 function (small molecules) are also described. Finally, clinical trials testing the safety and efficacy of monoclonal antibodies to PCSK9 are reviewed. These have shown dose-dependent decreases in LDL cholesterol (44%–65%), apolipoprotein B (48%–59%), and lipoprotein(a) (27%–50%) without major adverse effects in various high-risk patient categories, including those with statin intolerance. Initial reports from 2 of these trials have indicated the expected reduction in cardiovascular events. Hence, inhibition of PCSK9 holds considerable promise as a therapeutic option for decreasing cardiovascular disease risk.

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Research works printed but not linked: 130

  1. 10.1161/01.cir.0000437738.63853.7a · DOI · Paper page
  2. 10.1161/01.ATV.0000134621.14315.43 · DOI · Paper page
  3. 10.1016/j.jacc.2008.08.039 · DOI · Paper page
  4. 10.1002/14651858.CD004816.pub5 · DOI · Paper page
  5. 10.1016/j.atherosclerosis.2014.10.105 · DOI
  6. 10.1155/2012/861924 · DOI
  7. 10.1161/STROKEAHA.113.004229 · DOI
  8. 10.1016/j.amjcard.2013.03.041 · DOI
  9. 10.1093/eurheartj/ehv043 · DOI · Paper page
  10. 10.1001/jama.2011.860 · DOI · Paper page
  11. 10.1074/jbc.M702027200 · DOI · Paper page
  12. 10.1073/pnas.0409736102 · DOI · Paper page
  13. 10.1194/jlr.M700437-JLR200 · DOI
  14. 10.1194/jlr.M008144 · DOI · Paper page
  15. 10.1016/j.abb.2003.09.011 · DOI
  16. 10.1073/pnas.0335507100 · DOI · Paper page
  17. 10.1038/ng1161 · DOI · Paper page
  18. 10.1073/pnas.0402133101 · DOI · Paper page
  19. 10.1074/jbc.M410077200 · DOI · Paper page
  20. 10.1038/nsmb1235 · DOI · Paper page
  21. 10.1074/jbc.M606495200 · DOI · Paper page
  22. 10.1074/jbc.M110.192104 · DOI · Paper page
  23. 10.1002/humu.20882 · DOI
  24. 10.1007/s00439-003-1071-9 · DOI
  25. 10.1093/hmg/ddl077 · DOI · Paper page
  26. 10.1086/500615 · DOI · Paper page
  27. 10.1016/j.cjca.2013.03.004 · DOI
  28. 10.1161/01.ATV.0000204337.81286.1c · DOI · Paper page
  29. 10.1016/j.atherosclerosis.2006.12.035 · DOI
  30. 10.1016/j.jacc.2010.02.044 · DOI
  31. 10.1373/clinchem.2011.165191 · DOI · Paper page
  32. 10.1074/jbc.M114.594861 · DOI
  33. 10.1016/j.atherosclerosis.2006.08.039 · DOI
  34. 10.1086/507488 · DOI
  35. 10.2174/1389202911314050010 · DOI
  36. 10.1073/pnas.0806312105 · DOI · Paper page
  37. 10.1074/jbc.M409699200 · DOI · Paper page
  38. 10.1074/jbc.C700095200 · DOI · Paper page
  39. 10.1074/jbc.M109.037085 · DOI · Paper page
  40. 10.1073/pnas.0712064105 · DOI · Paper page
  41. 10.1074/jbc.M110.199042 · DOI · Paper page
  42. 10.1074/jbc.M113.453373 · DOI · Paper page
  43. 10.1371/journal.pone.0125127 · DOI
  44. Tuli A, Sharma M, McIlhaney MM, Talmadge JE, Naslavsky N, Caplan S, Solheim JC. Amyloid precursor-like protein 2 increases the endocytosis, instability, and turnover of the H2-K(d) MHC class I molecule. J Immunol. 2008;181:1978–1987. · DOI
  45. 10.1161/CIRCULATIONAHA.113.006720 · DOI
  46. 10.1161/ATVBAHA.108.181586 · DOI
  47. 10.1042/CS20140559 · DOI
  48. 10.1053/j.gastro.2007.06.019 · DOI
  49. 10.1161/ATVBAHA.112.300263 · DOI
  50. 10.5551/jat.11.200 · DOI
  51. 10.1152/ajpgi.90424.2008 · DOI
  52. 10.1161/ATVBAHA.110.220988 · DOI · Paper page
  53. 10.1016/j.atherosclerosis.2014.07.010 · DOI · Paper page
  54. 10.1186/1750-1326-6-30 · DOI · Paper page
  55. 10.1016/j.bbrc.2008.07.106 · DOI · Paper page
  56. 10.1111/j.1471-4159.2006.03928.x · DOI · Paper page
  57. 10.1007/s40264-015-0296-6 · DOI
  58. 10.1002/pds.3381 · DOI
  59. 10.1056/NEJMoa1501031 · DOI · Paper page
  60. 10.2337/db07-0056 · DOI
  61. 10.1074/jbc.M300102200 · DOI
  62. 10.1097/MOL.0000000000000180 · DOI
  63. 10.1111/1753-0407.12139 · DOI
  64. 10.1016/j.febslet.2009.12.018 · DOI
  65. 10.1126/scitranslmed.3008782 · DOI
  66. 10.1016/j.amjmed.2014.10.057 · DOI
  67. 10.5551/jat.14936 · DOI
  68. 10.1161/ATVBAHA.114.303284 · DOI · Paper page
  69. 10.1161/ATVBAHA.113.302401 · DOI
  70. 10.1161/circ.130.suppl_2.15525 · DOI
  71. 10.1161/01.ATV.16.6.794 · DOI
  72. 10.1001/jama.2009.1063 · DOI · Paper page
  73. 10.1016/j.amjcard.2014.05.060 · DOI
  74. 10.1016/j.jacc.2014.01.006 · DOI
  75. 10.1074/jbc.M114.611988 · DOI · Paper page
  76. 10.1097/MOL.0000000000000070 · DOI
  77. 10.1161/ATVBAHA.112.250043 · DOI
  78. 10.1038/sj.ki.5002131 · DOI
  79. 10.1194/jlr.M038877 · DOI · Paper page
  80. 10.1177/1074248414539562 · DOI
  81. 10.1517/14728220802600715 · DOI · Paper page
  82. 10.1161/CIRCRESAHA.114.301621 · DOI
  83. Harding FA, Stickler MM, Razo J, DuBridge RB. The immunogenicity of humanized and fully human antibodies: residual immunogenicity resides in the CDR regions. MAbs. 2010;2:256–265. · DOI
  84. 10.1038/nrcardio.2014.84 · DOI
  85. 10.1016/j.ijcard.2014.06.049 · DOI
  86. 10.1016/j.jacl.2014.09.007 · DOI · Paper page
  87. Moriarty PM, Thompson PD, Cannon CP, Guyton JR, Bergeron J, Zieve FJ, Bruckert E, Jacobson TA, Baccara-Dinet MT, Zhao J, Pordy R, Gipe D. Late-Breaking Clinical Trial Abstracts: ODYSSEY ALTERNATIVE: efficacy and safety of the proprotein convertase subtilisin/kexin type 9 monoclonal antibody, alirocumab, versus ezetimibe, in patients with statin intolerance as defined by a placebo run-in and statin rechallenge arm. Circulation. 2014;130:2105–2126. · DOI
  88. 10.1093/eurheartj/ehv028 · DOI
  89. Goemann IM, Londero TM, Dora JM. PCSK9 inhibitors and cardiovascular events. N Engl J Med. 2015;373:773–774. · DOI
  90. 10.1016/j.jacc.2014.03.018 · DOI · Paper page
  91. 10.1016/j.jacc.2014.03.019 · DOI · Paper page
  92. 10.1001/jama.2014.4030 · DOI · Paper page
  93. 10.1016/S0140-6736(14)61374-X · DOI
  94. 10.1016/j.amjcard.2015.02.006 · DOI
  95. 10.1016/j.jacc.2012.08.986 · DOI
  96. 10.1056/NEJMoa1201832 · DOI
  97. 10.1016/j.jacc.2012.03.007 · DOI
  98. 10.1016/S0140-6736(12)60771-5 · DOI
  99. 10.1016/S0140-6736(12)61770-X · DOI
  100. 10.1016/S0140-6736(12)61771-1 · DOI
  101. 10.1161/CIRCULATIONAHA.112.144055 · DOI
  102. Gumbiner B JT, Udata C, Forgues P, Baum C, Garzone P. Effects of 12 weeks of treatment with RN316 (PF-04950615), a humanized IgG2Δa monoclonal antibody binding proprotein convertase subtilisin kexin type 9, in hypercholesterolemic subjects on high and maximal dose statins. Circulation. 2012:2776–2799.
  103. 10.1002/clc.22327 · DOI
  104. Bays H, Farnier M, Gaudet D, Weiss R, Ruiz JL, Watts GF, Gouni Berthold I, Robinson JG, Jones PH, Severance R, Averna M, Steinhagen-Thiessen E, Colhoun HM, Zhao J, Du Y, Hanotin C, Donahue S. Late-Breaking Clinical Trial Abstracts: efficacy and safety of combining alirocumab with atorvastatin or rosuvastatin versus statin intensification or adding ezetimibe in high cardiovascular risk patients: ODYSSEY OPTIONS I and II. Circulation. 2014;130:2105–2126. · DOI
  105. 10.1007/s10557-014-6523-z · DOI
  106. Ginsberg HN, Rader DJ, Raal FJ, Guyton JR, Lorenzato C, Pordy R, Baccara-Dinet MT, Stroes ES. Late-Breaking Clinical Trial Abstracts: ODYSSEY HIGH FH: efficacy and safety of alirocumab in patients with severe heterozygous familial hypercholesterolemia. Circulation. 2014;130:2105–2126. · DOI
  107. Stroes E, Guyton J, Farnier M, Rader D, Moriarty P, Bergeron J, Langslet G, Lepor N, Civeira F, Gaudet D, Watts G, Manvelian G, Lecorps G, Zhao J, Baccara-Dinet M, Roth E. Efficacy and safety of alirocumab 150 mg and 300 mg every 4 weeks in patients with poorly controlled hypercholesterolemia: the ODYSSEY CHOICE I and CHOICE II studies [abstract]. J Am Coll Cardiol. 2015;65. · DOI
  108. 10.1073/pnas.0805434105 · DOI
  109. 10.1074/jbc.M808363200 · DOI
  110. 10.1074/jbc.M808802200 · DOI
  111. 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. · DOI
  112. 10.1074/jbc.M111.273474 · DOI
  113. 10.1074/jbc.M113.514067 · DOI
  114. 10.1074/jbc.M805971200 · DOI · Paper page
  115. 10.1371/journal.pone.0041865 · DOI · Paper page
  116. 10.1093/protein/gzq097 · DOI
  117. 10.1124/jpet.114.214221 · DOI
  118. 10.1016/j.jhep.2013.05.045 · DOI
  119. 10.1194/jlr.C600025-JLR200 · DOI
  120. 10.1016/j.ddtec.2005.08.012 · DOI
  121. 10.1038/nature06783 · DOI · Paper page
  122. 10.1371/journal.pone.0010682 · DOI · Paper page
  123. 10.1038/mt.2011.260 · DOI
  124. 10.1053/j.ajkd.2013.02.359 · DOI
  125. 10.1016/j.yjmcc.2015.03.009 · DOI
  126. 10.1038/embor.2011.205 · DOI · Paper page
  127. 10.1371/journal.pone.0072113 · DOI
  128. 10.1097/FPC.0000000000000081 · DOI
  129. 10.1097/FPC.0000000000000120 · DOI
  130. 10.1093/hmg/dds559 · DOI · Paper page

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Metadata

Authors
Bergeron, N., Phan, B. A. P., Ding, Y., Fong, A., & Krauss, R. M.
Affiliations
From Children’s Hospital Oakland Research Institute, CA (N.B., R.M.K.); Touro University, College of Pharmacy, Vallejo, CA (N.B., Y.D., A.F.); and University of California, San Francisco (B.A.P.P., R.M.K.).
Venue
Circulation
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2015-10-27
Volume
132
Issue
17
Pages
1648-1666
ISSN
  • 0009-7322
  • 1524-4539
DOI
10.1161/circulationaha.115.016080
Cited by
171
References
15
Language
en

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