Inhibition of PCSK9 does not improve lipopolysaccharide-induced mortality in mice

Journal of Lipid Research

Volumn 58, Issue 8, 2017, Pages 1661-1669

  Berger, Jean Mathieu ^a   Valdes, Angel Loza ^a   Gromada, Jesper ^c   Anderson, Norma ^a   Horton, Jay D ^a,b  

^a UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

^b UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

^c REGENERON PHARMACEUTICALS INC   (United States)

Author keywords

Cholesterol; Endotoxemia; LDL; Lipopolysaccharide; PCSK9

Indexed keywords

ALIROCUMAB; APOLIPOPROTEIN B100; CHOLESTEROL ESTER TRANSFER PROTEIN; INTERLEUKIN 10; INTERLEUKIN 6; INTERLEUKIN 8; LIPOPOLYSACCHARIDE; LOW DENSITY LIPOPROTEIN CHOLESTEROL; LOW DENSITY LIPOPROTEIN RECEPTOR; MACROPHAGE INFLAMMATORY PROTEIN 2; PROPROTEIN CONVERTASE 9; TUMOR NECROSIS FACTOR; MONOCLONAL ANTIBODY; PCSK9 PROTEIN, MOUSE; PROTEINASE INHIBITOR;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CHOLESTEROL BLOOD LEVEL; CONTROLLED STUDY; DRUG EFFICACY; ENDOTOXEMIA; ENZYME INHIBITION; GENE DELETION; GERMLINE MUTATION; HUMAN; LETHAL DOSE; LIPOPOLYSACCHARIDE-INDUCED ENDOTOXEMIA; LOSS OF FUNCTION MUTATION; MALE; MORTALITY RATE; MOUSE; NONHUMAN; PCSK9 GENE; PRIORITY JOURNAL; PROTEIN EXPRESSION; SURVIVAL RATE; ANIMAL; ANTAGONISTS AND INHIBITORS; BLOOD; COHORT ANALYSIS; SURVIVAL ANALYSIS;

ANIMALS; ANTIBODIES, MONOCLONAL; CHOLESTEROL, LDL; COHORT STUDIES; HUMANS; LIPOPOLYSACCHARIDES; MICE; PROPROTEIN CONVERTASE 9; PROTEASE INHIBITORS; SURVIVAL ANALYSIS;

EID: 85026728779     PISSN: 00222275     EISSN: 15397262     Source Type: Journal    
DOI: 10.1194/jlr.M076844     Document Type: Article

References (40)

1. Lagace, T. A., D. E. Curtis, R. Garuti, M. C. McNutt, S. W. Park, H. B. Prather, N. N. Anderson, Y. K. Ho, R. E. Hammer, and J. D. Horton. 2006. Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice. J. Clin. Invest. 116: 2995–3005.
2. Grefhorst, A., M. C. McNutt, T. A. Lagace, and J. D. Horton. 2008. Plasma PCSK9 preferentially reduces liver LDL receptors in mice. J. Lipid Res. 49: 1303–1311.
3. Chen, S. N., C. M. Ballantyne, A. M. Gotto, Jr., Y. Tan, J. T. Willerson, and A. J. Marian. 2005. A common PCSK9 haplotype, encompassing the E670G coding single nucleotide polymorphism, is a novel genetic marker for plasma low-density lipoprotein cholesterol levels and severity of coronary atherosclerosis. J. Am. Coll. Cardiol. 45: 1611–1619
4. Cohen, J., A. Pertsemlidis, I. K. Kotowski, R. Graham, C. K. Garcia, and H. H. Hobbs. 2005. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat. Genet. 37: 161–165.
5. McKenney, J. M., M. J. Koren, D. J. Kereiakes, C. Hanotin, A-C. Ferrand, and E. A. Stein. 2012. 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: 2344–2353.
6. Stein, E. A., D. Gipe, J. Bergeron, D. Gaudet, R. Weiss, R. Dufour, R. Wu, and R. Pordy. 2012. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hyper-cholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet. 380: 29–36.
7. Roth, E. M., J. M. McKenney, C. Hanotin, G. Asset, and E. A. Stein. 2012. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N. Engl. J. Med. 367: 1891–1900.
8. Sullivan, D., A. G. Olsson, R. Scott, J. B. Kim, A. Xue, V. Gebski, S. M. Wasserman, and E. A. Stein. 2012. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA. 308: 2497–2506.
9. Roth, E. M., P. M. Moriarty, J. Bergeron, G. Langslet, G. Manvelian, J. Zhao, M. T. Baccara-Dinet, and D. J. Rader. 2016. A phase III randomized trial evaluating alirocumab 300 mg every 4 weeks as monotherapy or add-on to statin: ODYSSEY CHOICE I. Atherosclerosis. 254: 254–262.
10. Ridker, P. M., J. Revkin, P. Amarenco, R. Brunell, M. Curto, F. Civeira, M. Flather, R. J. Glynn, J. Gregoire, J. W. Jukema, et al. 2017. Cardiovascular efficacy and safety of bococizumab in high-risk patients. N. Engl. J. Med. 376: 1527–1539.
11. Sabatine, M. S., R. P. Giugliano, A. C. Keech, N. Honarpour, S. D. Wiviott, S. A. Murphy, J. F. Kuder, H. Wang, T. Liu, S. M. Wasserman, et al. 2017. Evolocumab and clinical outcomes in patients with cardiovascular disease. N. Engl. J. Med. 376: 1713–1722.
12. Horton, J. D., J. C. Cohen, and H. H. Hobbs. 2007. Molecular biology of PCSK9: its role in LDL metabolism. Trends Biochem. Sci. 32: 71–77.
13. Walley, K. R., K. R. Thain, J. A. Russell, M. P. Reilly, N. J. Meyer, J. F. Ferguson, J. D. Christie, T. Nakada, C. D. Fjell, S. A. Thair, et al. 2014. PCSK9 is a critical regulator of the innate immune response and septic shock outcome. Sci. Transl. Med. 6: 258ra143.
14. Boyd, J. H., C. D. Fjell, J. A. Russell, D. Sirounis, M. S. Cirstea, and K. R. Walley. 2016. Increased plasma PCSK9 levels are associated with reduced endotoxin clearance and the development of acute organ failures during sepsis. J. Innate Immun. 8: 211–220.
15. Dwivedi, D. J., P. M. Grin, M. Khan, A. Prat, J. Zhou, A. E. Fox-Robichaud, N. G. Seidah, and P. C. Liaw. 2016. Differential expression of PCSK9 modulates infection, inflammation and coagulation in a murine model of sepsis. Shock. 46: 672–680.
16. Feingold, K. R., A. H. Moser, J. K. Shigenaga, S. M. Patzek, and C. Grunfeld. 2008. Inflammation stimulates the expression of PCSK9. Biochem. Biophys. Res. Commun. 374: 341–344.
17. Angus, D. C., and T. van der Poll. 2013. Severe sepsis and septic shock. N. Engl. J. Med. 369: 840–851.
18. Feingold, K. R., and C. Grunfeld. 2010. The acute phase response inhibits reverse cholesterol transport. J. Lipid Res. 51: 682–684.
19. Tateda, K., T. Matsumoto, S. Miyazaki, and K. Yamaguchi. 1996. Lipopolysaccharide-induced lethality and cytokine production in aged mice. Infect. Immun. 64: 769–774.
20. Gautier, T., and L. Lagrost. 2011. Plasma PLTP (phospholipid-transfer protein): an emerging role in ‘reverse lipopolysaccharide transport’ and innate immunity. Biochem. Soc. Trans. 39: 984–988.
21. Levels, J. H. M., J. A. Marquart, P. R. Abraham, A. E. van den Ende, H. O. F. Molhuizen, S. J. H. van Deventer, and J. C. M. Meijers. 2005. Lipopolysaccharide is transferred from high-density to low-density lipoproteins by lipopolysaccharide-binding protein and phospho-lipid transfer protein. Infect. Immun. 73: 2321–2326.
22. Azzam, K. M., and M. B. Fessler. 2012. Crosstalk between reverse cholesterol transport and innate immunity. Trends Endocrinol. Metab. 23: 169–178.
23. Almog, Y., A. Shefer, V. Novack, N. Maimon, L. Barski, M. Eizinger, M. Friger, L. Zeller, and A. Danon. 2004. Prior statin therapy is associated with a decreased rate of severe sepsis. Circulation. 110: 880–885.
24. Rothberg, M. B., C. Bigelow, P. S. Pekow, and P. K. Lindenauer. 2012. Association between statins given in hospital and mortality in pneumonia patients. J. Gen. Intern. Med. 27: 280–286.
25. Donnino, M. W., M. N. Cocchi, M. Howell, P. Clardy, D. Talmor, L. Cataldo, M. Chase, A. Al-Marshad, L. Ngo, and N. I. Shapiro. 2009. Statin therapy is associated with decreased mortality in patients with infection. Acad. Emerg. Med. 16: 230–234.
26. Mortensen, E. M., M. I. Restrepo, L. A. Copeland, J. A. Pugh, A. Anzueto, J. E. Cornell, and M. J. V. Pugh. 2007. Impact of previous statin and angiotensin II receptor blocker use on mortality in patients hospitalized with sepsis. Pharmacotherapy. 27: 1619–1626.
27. Kruger, P., K. Fitzsimmons, D. Cook, M. Jones, and G. Nimmo. 2006. Statin therapy is associated with fewer deaths in patients with bacteraemia. Intensive Care Med. 32: 75–79.
28. Kruger, P. S., M. L. Harward, M. A. Jones, C. J. Joyce, K. M. Kostner, M. S. Roberts, and B. Venkatesh. 2011. Continuation of statin therapy in patients with presumed infection. Am. J. Respir. Crit. Care Med. 183: 774–781.
29. Kruger, P., M. Bailey, R. Bellomo, D. J. Cooper, M. Harward, A. Higgins, B. Howe, D. Jones, C. Joyce, K. Kostner, et al. 2013. A multicenter randomized trial of atorvastatin therapy in intensive care patients with severe sepsis. Am. J. Respir. Crit. Care Med. 187: 743–750.
30. Patel, J. M., C. Snaith, D. R. Thickett, L. Linhartova, T. Melody, P. Hawkey, A. H. Barnett, A. Jones, T. Hong, M. W. Cooke, et al. 2012. Randomized double-blind placebo-controlled trial of 40 mg/ day of atorvastatin in reducing the severity of sepsis in ward patients (ASEPSIS Trial). Crit. Care. 16: R231.
31. Papazian, L., A. Roch, P-E. Charles, C. Penot-Ragon, G. Perrin, P. Roulier, P. Goutorbe, J-Y. Lefrant, S. Wiramus, B. Jung, et al. 2013. Effect of statin therapy on mortality in patients with ventilator-associated pneumonia: a randomized clinical trial. JAMA. 310: 1692–1700.
32. Wan, Y-D., T-W. Sun, Q-C. Kan, F-X. Guan, and S-G. Zhang. 2014. Effect of statin therapy on mortality from infection and sepsis: a meta-analysis of randomized and observational studies. Crit. Care. 18: R71.
33. van den Hoek, H. L., W. J. W. Bos, A. de Boer, and E. M. W. van de Garde. 2011. Statins and prevention of infections: systematic review and meta-analysis of data from large randomised placebo controlled trials. BMJ. 343: d7281.
34. Thomas, G., S. Hraiech, A. Loundou, J. Truwit, P. Kruger, D. F. Mcauley, L. Papazian, and A. Roch. 2015. Statin therapy in critically-ill patients with severe sepsis: a review and meta-analysis of randomized clinical trials. Minerva Anestesiol. 81: 921–930.
35. Stein, E. A., S. Mellis, G. D. Yancopoulos, N. Stahl, D. Logan, W. B. Smith, E. Lisbon, M. Gutierrez, C. Webb, R. Wu, et al. 2012. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N. Engl. J. Med. 366: 1108–1118.
36. Rashid, S., D. E. Curtis, R. Garuti, N. N. Anderson, Y. Bashmakov, Y. K. Ho, R. E. Hammer, Y-A. Moon, and J. D. Horton. 2005. Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9. Proc. Natl. Acad. Sci. USA. 102: 5374–5379.
37. Hernandez, M., S. D. Wright, and T-Q. Cai. 2007. Critical role of cholesterol ester transfer protein in nicotinic acid-mediated HDL elevation in mice. Biochem. Biophys. Res. Commun. 355: 1075–1080.
38. Kozlitina, J., E. Smagris, S. Stender, B. G. Nordestgaard, H. H. Zhou, A. Tybjærg-Hansen, T. F. Vogt, H. H. Hobbs, and J. C. Cohen. 2014. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 46: 352–356.
39. Lakoski, S. G., T. A. Lagace, J. C. Cohen, J. D. Horton, and H. H. Hobbs. 2009. Genetic and metabolic determinants of plasma PCSK9 levels. J. Clin. Endocrinol. Metab. 94: 2537–2543.
40. Laubach, V. E., E. G. Shesely, O. Smithies, and P. A. Sherman. 1995. Mice lacking inducible nitric oxide synthase are not resistant to lipopolysaccharide-induced death. Proc. Natl. Acad. Sci. USA. 92: 10688–10692.