PCSK9 is a critical regulator of the innate immune response and septic shock outcome

Science Translational Medicine

Volumn 6, Issue 258, 2014, Pages 258ra143-

  Walley, Keith R ^a   Thain, Katherine R ^a   Russell, James A ^a   Reilly, Muredach P ^b   Meyer, Nuala J ^b   Ferguson, Jane F ^b   Christie, Jason D ^b   Nakada, Taka Aki ^c   Fjell, Chris D ^a   Thair, Simone A ^a   Cirstea, Mihai S ^a   Boyd, John H ^a  

^a UNIVERSITY OF BRITISH COLUMBIA   (Canada)

^b UNIVERSITY OF PENNSYLVANIA   (United States)

^c CHIBA UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

INTERLEUKIN 10; INTERLEUKIN 6; LIPOPOLYSACCHARIDE; LOW DENSITY LIPOPROTEIN RECEPTOR; MACROPHAGE INFLAMMATORY PROTEIN 2; MONOCYTE CHEMOTACTIC PROTEIN 1; PROPROTEIN CONVERTASE SUBTILISIN KESIN TYPE 9; SERINE PROTEINASE; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG; PCSK9 PROTEIN, HUMAN; PCSK9 PROTEIN, MOUSE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CONTROLLED STUDY; CYTOKINE PRODUCTION; CYTOKINE RESPONSE; DETOXIFICATION; GAIN OF FUNCTION MUTATION; GENE EXPRESSION REGULATION; GENETIC VARIABILITY; HEART LEFT VENTRICLE EJECTION FRACTION; HUMAN; HUMAN CELL; INFLAMMATION; INHIBITION KINETICS; INNATE IMMUNITY; LDLR GENE; LIVER CELL; LOSS OF FUNCTION MUTATION; MAJOR CLINICAL STUDY; MOUSE; NONHUMAN; PCSK9 GENE; PERITONITIS; POLYMICROBIAL PERITONITIS; PROTEIN EXPRESSION; SEPTIC SHOCK; SINGLE NUCLEOTIDE POLYMORPHISM; ANIMAL; C57BL MOUSE; DEFICIENCY; DISEASE MODEL; DRUG EFFECTS; GENETIC VARIATION; GENETICS; HEPG2 CELL LINE; IMMUNOLOGY; KNOCKOUT MOUSE; MALE; METABOLISM; RANDOMIZED CONTROLLED TRIAL;

ANIMALS; DISEASE MODELS, ANIMAL; GENETIC VARIATION; HEP G2 CELLS; HUMANS; IMMUNITY, INNATE; LIPOPOLYSACCHARIDES; MALE; MICE, INBRED C57BL; MICE, KNOCKOUT; PROPROTEIN CONVERTASES; SERINE ENDOPEPTIDASES; SHOCK, SEPTIC;

EID: 84908229451     PISSN: 19466234     EISSN: 19466242     Source Type: Journal    
DOI: 10.1126/scitranslmed.3008782     Document Type: Article

References (49)

1. J. H. Levels, P. R. Abraham, E. P. van Barreveld, J. C Meijers, S. J. van Deventer, Distribution and kinetics of lipoprotein-bound lipoteichoic acid. Infect. Immun. 71, 3280-3284 (2003).
2. P. A. Trinel, Y. Plancke, P. Gerold, T. Jouault, F. Delplace, R. T. Schwarz, G. Strecker, D. Poulain, The Candida albicans phospholipomannan is a family of glycolipids present in phosphoinosi-tolmannosides with long linear chains of ß-1, 2-linked mannose residues. J. Biol. Chem. 274, 30520-30526 (1999).
3. K. M. Azzam, M. B. Fessler, Crosstalk between reverse cholesterol transport and innate immunity. Trends Endocrinol. Metab. 23, 169-178 (2012).
4. P. Gallay, D. Heumann, D. Le Roy, C. Barras, M. P. Glauser, Mode of action of anti-lipopolysaccharide-binding protein antibodies for prevention of endotoxemic shock in mice. Proc. Natl. Acad. Sci. USA. 91, 7922-7926 (1994).
5. T. Gautier, L. Lagrost, Plasma PLTP (phospholipid-transfer protein): An emerging role in 'reverse lipopolysaccharide transport' and innate immunity. Biochem. Soc. Trans. 39, 984-988 (2011).
6. J. H. Levels, J. A. Marquart, P. R. Abraham, A. E.van den Ende, H.O. Molhuizen, S.J.van Deventer, J. C Meijers, Lipopolysaccharide is transferred from high-density to low-density lipoproteins by lipopolysaccharide-binding protein and phospholipid transfer protein. Infect. Immun. 73, 2321-2326 (2005).
7. E. Hailman, J. J. Albers, G. Wolfbauer, A. Y. Tu, S. D. Wright, Neutralization and transfer of lipopolysaccharide by phospholipid transfer protein. J. Biol. Chem. 271, 12172-12178 (1996).
8. T. Gautier, A. Klein, V. Deckert, C. Desrumaux, N. Ogier, A. L. Sberna, C. Paul, N. Le Guern, A. Athias, T. Montange, S. Monier, F. Piard, X. C. Jiang, D. Masson, L. Lagrost, Effect of plasma phospholipid transfer protein deficiency on lethal endotoxemia in mice. J. Biol. Chem. 283, 18702-18710 (2008).
9. M. C. McNutt, H. J. Kwon, C. Chen, J. R. Chen, J. D. Horton, T. A. Lagace, Antagonism of secreted PCSK9 increases low density lipoprotein receptor expression in HepG2 cells. J. Biol. Chem. 284, 10561-10570 (2009).
10. K. Tveten, T. B. Strøm, K. E. Berge, T. P. Leren, PCSK9-mediated degradation of the LDL receptor generates a 17 kDa C-terminal LDL receptor fragment. J. Lipid Res. 54, 1560-1566 (2013).
11. L. Zhang, T. McCabe, J. H. Condra, Y. G. Ni, L. B. Peterson, W. Wang, A. M. Strack, F. Wang, S. Pandit, H. Hammond, D. Wood, D. Lewis, R. Rosa, V. Mendoza, A. M. Cumiskey, D. G. Johns, B. C. Hansen, X. Shen, N. Geoghagen, K. Jensen, L. Zhu, K. Wietecha, D. Wisniewski, L. Huang, J. Z. Zhao, R. Ernst, R. Hampton, P. Haytko, F. Ansbro, S. Chilewski, J. Chin, L. J. Mitnaul, A. Pellacani, C. P. Sparrow, Z. An, W. Strohl, B. Hubbard, A. S. Plump, D. Blom, A. Sitlani, An anti-PCSK9 antibody reduces LDL-cholesterol on top of a statin and suppresses hepatocyte SREBP-regulated genes. Int. J. Biol. Sci. 8, 310-327 (2012).
12. J. C. Cohen, E. Boerwinkle, T. H. Mosley Jr., H. H. Hobbs, Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N. Engl. J. Med. 354, 1264-1272 (2006).
13. J. D. Horton, J. C. Cohen, H. H. Hobbs, Molecular biology of PCSK9: Its role in LDL metabolism. Trends Biochem. Sci. 32, 71-77 (2007).
14. S. Kathiresan; Myocardial Infarction Genetics Consortium, A PCSK9 missense variant associated with a reduced risk of early-onset myocardial infarction. N. Engl. J. Med. 358, 2299-2300 (2008).
15. I. K. Kotowski, A. Pertsemlidis, A. Luke, R. S. Cooper, G. L. Vega, J. C. Cohen, H. H. Hobbs, A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol. Am. J. Hum. Genet. 78, 410-422 (2006).
16. K. Musunuru, G. Lettre, T. Young, D. N. Farlow, J. P. Pirruccello, K. G. Ejebe, B. J. Keating, Q. Yang, M. H. Chen, N. Lapchyk, A. Crenshaw, L. Ziaugra, A. Rachupka, E. J. Benjamin, L. A. Cupples, M. Fornage, E. R. Fox, S. R. Heckbert, J. N. Hirschhorn, C. Newton-Cheh, M. M. Nizzari, D. N. Paltoo, G. J. Papanicolaou, S. R. Patel, B. M. Psaty, D. J. Rader, S. Redline, S. S. Rich, J. I. Rotter, H. A. Taylor Jr., R. P. Tracy, R. S. Vasan, J. G. Wilson, S. Kathiresan, R. R. Fabsitz, E. Boerwinkle, S. B. Gabriel; NHLBI Candidate Gene Association Resource, Candidate gene association resource (CARe): Design, methods, and proof of concept. Circ. Cardiovasc. Genet. 3, 267-275 (2010).
17. M. Scartezini, C. Hubbart, R. A. Whittall, J. A. Cooper, A. H. Neil, S. E. Humphries, The PCSK9 gene R46L variant is associated with lower plasma lipid levels and cardiovascular risk in healthy U.K. men. Clin. Sci. 113, 435-441 (2007).
18. P. J. Talmud, F. Drenos, S. Shah, T. Shah, J. Palmen, C. Verzilli, T. R. Gaunt, J. Pallas, R. Lovering, K. Li, J. P. Casas, R. Sofat, M. Kumari, S. Rodriguez, T. Johnson, S. J. Newhouse, A. Dominiczak, N. J. Samani, M. Caulfield, P. Sever, A. Stanton, D. C. Shields, S. Padmanabhan, O. Melander, C. Hastie, C. Delles, S. Ebrahim, M. G. Marmot, G. D. Smith, D. A. Lawlor, P. B. Munroe, I. N. Day, M. Kivimaki, J. Whittaker, S. E. Humphries, A. D. Hingorani; ASCOT investigators, NORDIL investigators, BRIGHT Consortium, Gene-centric association signals for lipids and apolipo-proteins identified via the HumanCVD BeadChip. Am. J. Hum. Genet. 85, 628-642 (2009).
19. D. Cunningham, D. E. Danley, K. F. Geoghegan, M. C. Griffor, J. L. Hawkins, T. A. Subashi, A. H. Varghese, M. J. Ammirati, J. S. Culp, L. R. Hoth, M. N. Mansour, K. M. McGrath, A. P. Seddon, S. Shenolikar, K. J. Stutzman-Engwall, L. C. Warren, D. Xia, X. Qiu, Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia. Nat. Struct. Mol. Biol. 14, 413-419 (2007).
20. D. Steinberg, J. L. Witztum, Inhibition of PCSK9: A powerful weapon for achieving ideal LDL cholesterol levels. Proc. Natl. Acad. Sci. U.S.A. 106, 9546-9547 (2009).
21. Myocardial Infarction Genetics Consortium, S. Kathiresan, B. F. Voight, S. Purcell, K. Musunuru, D. Ardissino, P. M. Mannucci, S. Anand, J. C. Engert, N. J. Samani, H. Schunkert, J. Erdmann, M. P. Reilly, D. J. Rader, T. Morgan, J. A. Spertus, M. Stoll, D. Girelli, P. P. McKeown, C. C. Patterson, D. S. Siscovick, C. J. O'Donnell, R. Elosua, L. Peltonen, V. Salomaa, S. M. Schwartz, O. Melander, D. Altshuler, D. Ardissino, P. A. Merlini, C. Berzuini, L. Bernardinelli, F. Peyvandi, M. Tubaro, P. Celli, M. Ferrario, R. Fetiveau, N. Marziliano, G. Casari, M. Galli, F. Ribichini, M. Rossi, F. Bernardi, P. Zonzin, A. Piazza, P. M. Mannucci, S. M. Schwartz, D. S. Siscovick, J. Yee, Y. Friedlander, R. Elosua, J. Marrugat, G. Lucas, I. Subirana, J. Sala, R. Ramos, S. Kathiresan, J. B. Meigs, G. Williams, D. M. Nathan, C. A. MacRae, C. J. O'Donnell, V. Salomaa, A. S. Havulinna, L. Peltonen, O. Melander, G. Berglund, B. F. Voight, S. Kathiresan, J. N. Hirschhorn, R. Asselta, S. Duga, M. Spreafico, K. Musunuru, M. J. Daly, S. Purcell, B. F. Voight, S. Purcell, J. Nemesh, J. M. Korn, S. A. McCarroll, S. M. Schwartz, J. Yee, S. Kathiresan, G. Lucas, I. Subirana, R. Elosua, A. Surti, C. Guiducci, L. Gianniny, D. Mirel, M. Parkin, N. Burtt, S. B. Gabriel, N. J. Samani, J. R. Thompson, P. S. Braund, B. J. Wright, A. J. Balmforth, S. G. Ball, A. S. Hall; Wellcome Trust Case Control Consortium, H. Schunkert, J. Erdmann, P. Linsel-Nitschke, W. Lieb, A. Ziegler, I. König, C. Hengstenberg, M. Fischer, K. Stark, A. Grosshennig, M. Preuss, H. E. Wichmann, S. Schreiber, H. Schunkert, N. J. Samani, J. Erdmann, W. Ouwehand, C. Hengstenberg, P. Deloukas, M. Scholz, F. Cambien, M. P. Reilly, M. Li, Z. Chen, R. Wilensky, W. Matthai, A. Qasim, H. H. Hakonarson, J. Devaney, M. S. Burnett, A. D. Pichard, K. M. Kent, L. Satler, J. M. Lindsay, R. Waksman, C. W. Knouff, D. M. Waterworth, M. C. Walker, V. Mooser, S. E. Epstein, D. J. Rader, T. Scheffold, K. Berger, M. Stoll, A. Huge, D. Girelli, N. Martinelli, O. Olivieri, R. Corrocher, T. Morgan, J. A. Spertus, P. McKeown, C C. Patterson, H. Schunkert, E. Erdmann, P. Linsel-Nitschke, W. Lieb, A. Ziegler, I. R. König, C. Hengstenberg, M. Fischer, K. Stark, A. Grosshennig, M. Preuss, H. E. Wichmann, S. Schreiber, H. Hólm, G. Thorleifsson, U. Thorsteinsdottir, K. Stefansson, J. C. Engert, R. Do, C. Xie, S. Anand, S. Kathiresan, D. Ardissino, P. M. Mannucci, D. Siscovick, C. J. O'Donnell, N. J. Samani, O. Melander, R. Elosua, L. Peltonen, V. Salomaa, S. M. Schwartz, D. Altshuler, Genome-wide association of early-onset myocardial infarction with single nu cleotide polymorphisms and copy number variants. Nat. Genet. 41, 334-341 (2009).
22. A. King, Lipids. Antibodies against PCSK9-A new era of therapy. Nat. Rev. Cardiol. 10, 1 (2013).
23. J. H. Boyd, B. Kan, H. Roberts, Y. Wang, K. R. Walley, S100A8 and S100A9 mediate endotoxin-induced cardiomyocyte dysfunction via the receptor for advanced glycation end products. Circ. Res. 102, 1239-1246 (2008).
24. J. H. Boyd, S. Mathur, Y. Wang, R. M. Bateman, K. R. Walley, Toll-like receptor stimulation in cardiomyoctes decreases contractility and initiates an NF-KB dependent inflammatory response. Cardiovasc. Res. 72, 384-393 (2006).
25. M. J. Scott, S. Liu, R. A. Shapiro, Y. Vodovotz, T. R. Billiar, Endotoxin uptake in mouse liver is blocked by endotoxin pretreatment through a suppressor of cytokine signaling-1-dependent mechanism. Hepatology 49, 1695-1708 (2009).
26. T. A. Lagace, D. E. Curtis, R. Garuti, M. C. McNutt, S. W. Park, H. B. Prather, N. N. Anderson, Y. K. Ho, R. E. Hammer, J. D. Horton, Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice. J. Clin. Invest. 116, 2995-3005 (2006).
27. N. Lyle, J. Boyd, The potential for PCR based testing to improve diagnosis and treatment of sepsis. Curr. Infect. Dis. Rep. 15, 372-379 (2013).
28. J. H. Boyd, J. A. Russell, C. D. Fjell, The meta-genome of sepsis: Host genetics, pathogens and the acute immune response. J. Innate Immun. 6, 272-283 (2014).
29. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit. Care Med. 20, 864-874 (1992).
30. J. A. Russell, K. R. Walley, J. Singer, A. C. Gordon, P. C. Hébert, D. J. Cooper, C. L. Holmes, S. Mehta, J. T. Granton, M. M. Storms, D. J. Cook, J. J. Presneill, D. Ayers; VASST Investigators, Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl. J. Med. 358, 877-887 (2008).
31. J. Mayne, T. C. Ooi, A. Raymond, M. Cousins, L. Bernier, T. Dewpura, F. Sirois, M. Mbikay, J. Davignon, M. Chrétien, Differential effects of PCSK9 loss of function variants on serum lipid and PCSK9 levels in Caucasian and African Canadian populations. Lipids Health Dis. 12, 70 (2013).
32. A. K. Soutar, R. P. Naoumova, Mechanisms of disease: Genetic causes of familial hypercholesterolemia. Nat. Clin. Pract. Cardiovasc. Med. 4, 214-225 (2007).
33. S. Rashid, D. E. Curtis, R. Garuti, N. N. Anderson, Y. Bashmakov, Y. K. Ho, R. E. Hammer, Y. A. Moon, J. D. Horton, Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9. Proc. Nat. Acad. Sci. U.S.A. 102, 5374-5379 (2005).
34. J. Cameron, T. Ranheim, M. A. Kulseth, T. P. Leren, K. E. Berge, Berberine decreases PCSK9 expression in HepG2 cells. Atherosclerosis 201, 266-273 (2008).
35. H. B. Xiao, Z. L. Sun, H. B. Zhang, D. S. Zhang, Berberine inhibits dyslipidemia in C57BL/6 mice with lipopolysaccharide induced inflammation. Pharmacol. Rep. 64, 889-895 (2012).
36. F. Gao, H. E. Ihn, M. W. Medina, R. M. Krauss, A common polymorphism in the LDL receptor gene has multiple effects on LDL receptor function. Hum. Mol. Genetics 22, 1424-1431 (2013).
37. K. Shioji, T. Mannami, Y. Kokubo, N. Inamoto, S. Takagi, Y. Goto, H. Nonogi, N. Iwai, Genetic variants in PCSK9 affect the cholesterol level in Japanese. J. Hum. Genet. 49, 109-114 (2004).
38. S. N. Chen, C. M. Ballantyne, A. M. Gotto Jr., Y. Tan, J. T. Willerson, A. J. Marian, 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 (2005).
39. A. Kumar, D. Roberts, K. E.Wood, B. Light, J. E. Parrillo, S. Sharma, R. Suppes, D. Feinstein, S. Zanotti, L. Taiberg, D. Gurka, A. Kumar, M. Cheang, Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit. Care Med. 34, 1589-1596 (2006).
40. P. T. Kovanen, D.W. Bilheimer, J. L. Goldstein, J. J. Jaramillo, M.S. Brown, Regulatory role for hepatic low density lipoprotein receptors in vivo in the dog. Proc. Nat. Acad. Sci. U.S.A. 78, 1194-1198 (1981).
41. A. Pocathikorn, R. R. Taylor, C. D. Mamotte, Atorvastatin increases expression of low-density lipoprotein receptor mRNA in human circulating mononuclear cells. Clin. Exp. Pharmacol. Physiol. 37, 471-476 (2010).
42. W. A. Flegel, M. W. Baumstark, C. Weinstock, A. Berg, H. Northoff, Prevention of endotoxin-induced monokine release by human low-and high-density lipoproteins and by apo-lipoprotein A-I. Infect. Immun. 61, 5140-5146 (1993).
43. V. Novack, J. MacFadyen, A. Malhotra, Y. Almog, R. J. Glynn, P. M. Ridker, The effect of rosuvastatin on incident pneumonia: Results from the JUPITER trial. CMAJ 184, E367-E372 (2012).
44. M. B. Rothberg, C. Bigelow, P. S. Pekow, P. K. Lindenauer, Association between statins given in hospital and mortality in pneumonia patients. J. Gen. Intern. Med. 27, 280-286 (2012).
45. P. S. Kruger, M. L. Harward, M. A. Jones, C. J. Joyce, K. M. Kostner, M. S. Roberts, B. Venkatesh, Continuation of statin therapy in patients with presumed infection: A randomized controlled trial. Am. J. Respir. Crit. Care Med. 183, 774-781 (2011).
46. K. R. Walley, N. W. Lukacs, T. J. Standiford, R. M. Strieter, S. L. Kunkel, Balance of inflammatory cytokines related to severity and mortality of murine sepsis. Infect.Immun.64, 4733-4738 (1996).
47. M. A. Nadkarni, F. E. Martin, N. A. Jacques, N. Hunter, Determination of bacterial load by real-time PCR using a broad-range (universal) probe and primers set. Microbiology 148, 257-266 (2002).
48. H. Li, B. Dong, S. W. Park, H. S. Lee, W. Chen, J. Liu, Hepatocyte nuclear factor 1a plays a critical role in PCSK9 gene transcription and regulation by the natural hypocholesterolemic compound berberine. J. Biol. Chem. 284, 28885-28895 (2009).
49. J. F. Ferguson, P. N. Patel, R. Y. Shah, C. K. Mulvey, R. Gadi, P. S. Nijjar, H. M. Usman, N. N. Mehta, R. Shah, S. R. Master, K. J. Propert, M. P. Reilly, Race and gender variation in response to evoked inflammation. J. Transl. Med. 11, 63 (2013).