Local effects of human PCSK9 on the atherosclerotic lesion

Journal of Pathology

Volumn 238, Issue 1, 2016, Pages 52-62

  Giunzioni, Ilaria ^a   Tavori, Hagai ^a   Covarrubias, Roman ^c   Major, Amy S ^c   Ding, Lei ^b   Zhang, Youmin ^b   Devay, Rachel M ^d   Hong, Liang ^d   Fan, Daping ^e   Predazzi, Irene M ^a   Rashid, Shirya ^f   Linton, Macrae F ^b,c   Fazio, Sergio ^a  

^a OREGON HEALTH AND SCIENCE UNIVERSITY   (United States)

^b VANDERBILT UNIVERSITY   (United States)

^c VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

^d PFIZER INC   (United States)

^e UNIVERSITY OF SOUTH CAROLINA SCHOOL OF MEDICINE   (United States)

^f DALHOUSIE UNIVERSITY   (Canada)

Author keywords

atherosclerotic lesion; inflammation; LDLR; macrophages; mouse models; PCSK9

Indexed keywords

CHOLESTEROL; MESSENGER RNA; PROPROTEIN CONVERTASE SUBTILISIN KEXIN TYPE 9; PROTEIN; UNCLASSIFIED DRUG; LOW DENSITY LIPOPROTEIN RECEPTOR; PCSK9 PROTEIN, HUMAN; PROPROTEIN CONVERTASE 9; SERINE PROTEINASE;

ANIMAL CELL; ARTICLE; ATHEROGENESIS; ATHEROSCLEROSIS; BONE MARROW; CELL COUNT; CELL INFILTRATION; CHOLESTEROL BLOOD LEVEL; CONTROLLED STUDY; HUMAN; IN VITRO STUDY; INFLAMMATION; LIPID DIET; MONOCYTE; MOUSE; NONHUMAN; PERITONEUM MACROPHAGE; PRIORITY JOURNAL; PROTEIN EXPRESSION; ANIMAL; C57BL MOUSE; DISEASE MODEL; FLOW CYTOMETRY; FLUORESCENT ANTIBODY TECHNIQUE; HISTOCOMPATIBILITY; IMMUNOHISTOCHEMISTRY; IMMUNOPRECIPITATION; KNOCKOUT MOUSE; METABOLISM; PATHOLOGY; TRANSGENIC MOUSE;

ANIMALS; ATHEROSCLEROSIS; DISEASE MODELS, ANIMAL; FLOW CYTOMETRY; FLUORESCENT ANTIBODY TECHNIQUE; HUMANS; IMMUNOHISTOCHEMISTRY; IMMUNOPRECIPITATION; MACROPHAGES, PERITONEAL; MICE; MICE, INBRED C57BL; MICE, KNOCKOUT; MICE, TRANSGENIC; PROPROTEIN CONVERTASE 9; PROPROTEIN CONVERTASES; RECEPTORS, LDL; SERINE ENDOPEPTIDASES; TRANSPLANTATION CHIMERA;

EID: 84954425975     PISSN: 00223417     EISSN: 10969896     Source Type: Journal    
DOI: 10.1002/path.4630     Document Type: Article

References (51)

1. Abifadel M, Varret M, Rabes JP, et al., Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003; 34: 154-156.
2. Benjannet S, Rhainds D, Essalmani R, et al., 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: 48865-48875.
3. Lalanne F, Lambert G, Amar MJ, et al., Wild-type PCSK9 inhibits LDL clearance but does not affect apoB-containing lipoprotein production in mouse and cultured cells. J Lipid Res 2005; 46: 1312-1319.
4. Zaid A, Roubtsova A, Essalmani R, et al., Proprotein convertase subtilisin/kexin type 9 (PCSK9): hepatocyte-specific low-density lipoprotein receptor degradation and critical role in mouse liver regeneration. Hepatology 2008; 48: 646-654.
5. Poirier S, Mayer G, Poupon V, et al., Dissection of the endogenous cellular pathways of PCSK9-induced low density lipoprotein receptor degradation: evidence for an intracellular route. J Biol Chem 2009; 284: 28856-28864.
6. Tavori H, Fan D, Blakemore JL, et al., Serum proprotein convertase subtilisin/kexin type 9 and cell surface low-density lipoprotein receptor: evidence for a reciprocal regulation. Circulation 2013; 127: 2403-2413.
7. Canuel M, Sun X, Asselin MC, et al., Proprotein convertase subtilisin/kexin type 9 (PCSK9) can mediate degradation of the low density lipoprotein receptor-related protein 1 (LRP-1). PLoS One 2013; 8: e64145.
8. Poirier S, Mayer G, Benjannet S, et al., 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.
9. Overton CD, Yancey PG, Major AS, et al., Deletion of macrophage LDL receptor-related protein increases atherogenesis in the mouse. Circ Res 2007; 100: 670-677.
10. Yancey PG, Blakemore J, Ding L, et al., Macrophage LRP-1 controls plaque cellularity by regulating efferocytosis and Akt activation. Arterioscler Thromb Vasc Biol 2010; 30: 787-795.
11. Yancey PG, Ding Y, Fan D, et al., Low-density lipoprotein receptor-related protein 1 prevents early atherosclerosis by limiting lesional apoptosis and inflammatory Ly-6C-high monocytosis: evidence that the effects are not apolipoprotein E-dependent. Circulation 2011; 124: 454-464.
12. Ferri N, Tibolla G, Pirillo A, et al., Proprotein convertase subtilisin kexin type 9 (PCSK9) secreted by cultured smooth muscle cells reduces macrophages LDLR levels. Atherosclerosis 2011; 220: 381-386.
13. Swirski FK, Libby P, Aikawa E, et al., Ly-6χ monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J Clin Invest 2007; 117: 195-205.
14. Swirski FK, Pittet MJ, Kircher MF, et al., Monocyte accumulation in mouse atherogenesis is progressive and proportional to extent of disease. Proc Natl Acad Sci USA 2006; 103: 10340-10345.
15. Sunderkotter C, Nikolic T, Dillon MJ, et al., Subpopulations of mouse blood monocytes differ in maturation stage and inflammatory response. J Immunol 2004; 172: 4410-4417.
16. Liu G, Yang H,. Modulation of macrophage activation and programming in immunity. J Cell Physiol 2013; 228: 502-512.
17. Stout RD, Suttles J,. Functional plasticity of macrophages: reversible adaptation to changing microenvironments. J Leukoc Biol 2004; 76: 509-513.
18. Wesemann DR, Benveniste EN,. STAT-1α and IFNγ as modulators of TNFα signaling in macrophages: regulation and functional implications of the TNF receptor 1:STAT-1α complex. J Immunol 2003; 171: 5313-5319.
19. Li S, Guo YL, Xu RX, et al., Association of plasma PCSK9 levels with white blood cell count and its subsets in patients with stable coronary artery disease. Atherosclerosis 2014; 234: 441-445.
20. Tang Z, Jiang L, Peng J, et al., PCSK9 siRNA suppresses the inflammatory response induced by oxLDL through inhibition of NF-κB activation in THP-1-derived macrophages. Int J Mol Med 2012; 30: 931-938.
21. Kuhnast S, van der Hoorn JW, Pieterman EJ, et al., Alirocumab inhibits atherosclerosis, improves the plaque morphology, and enhances the effects of a statin. J Lipid Res 2014; 55: 2103-2112.
22. Fogelman AM, Haberland ME, Seager J, et al., Factors regulating the activities of the low density lipoprotein receptor and the scavenger receptor on human monocyte-macrophages. J Lipid Res 1981; 22: 1131-1141.
23. Hiltunen TP, Yla-Herttuala S,. Expression of lipoprotein receptors in atherosclerotic lesions. Atherosclerosis 1998; 137 (suppl): S81-88.
24. Linton MF, Babaev VR, Gleaves LA, et al., A direct role for the macrophage low density lipoprotein receptor in atherosclerotic lesion formation. J Biol Chem 1999; 274: 19204-19210.
25. Goldstein JL, Brown MS,. Regulation of low-density lipoprotein receptors: implications for pathogenesis and therapy of hypercholesterolemia and atherosclerosis. Circulation 1987; 76: 504-507.
26. Ason B, van der Hoorn JW, Chan J, et al., PCSK9 inhibition fails to alter hepatic LDLR, circulating cholesterol, and atherosclerosis in the absence of ApoE. J Lipid Res 2014; 55: 2370-2379.
27. Denis M, Marcinkiewicz J, Zaid A, et al., Gene inactivation of proprotein convertase subtilisin/kexin type 9 reduces atherosclerosis in mice. Circulation 2012; 125: 894-901.
28. Fan D, Yancey PG, Qiu S, et al., Self-association of human PCSK9 correlates with its LDLR-degrading activity. Biochemistry 2008; 47: 1631-1639.
29. Du F, Hui Y, Zhang M, et al., Novel domain interaction regulates secretion of proprotein convertase subtilisin/kexin type 9 (PCSK9) protein. J Biol Chem 2011; 286: 43054-43061.
30. Fazio S, Babaev VR, Murray AB, et al., Increased atherosclerosis in mice reconstituted with apolipoprotein E-null macrophages. Proc Natl Acad Sci USA 1997; 94: 4647-4652.
31. Linton MF, Atkinson JB, Fazio S,. Prevention of atherosclerosis in apolipoprotein E-deficient mice by bone marrow transplantation. Science 1995; 267: 1034-1037.
32. -ΔΔC t method. Methods 2001; 25: 402-408.
33. Forrest LM, Lough CM, Chung S, et al., Echium oil reduces plasma triglycerides by increasing intravascular lipolysis in apoB100-only low density lipoprotein (LDL) receptor knockout mice. Nutrients 2013; 5: 2629-2645.
34. Benoit M, Desnues B, Mege JL,. Macrophage polarization in bacterial infections. J Immunol 2008; 181: 3733-3739.
35. Strickland DK, Kounnas MZ, Argraves WS,. LDL receptor-related protein: a multiligand receptor for lipoprotein and proteinase catabolism. FASEB J 1995; 9: 890-898.
36. Maxwell KN, Breslow JL,. Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype. Proc Natl Acad Sci USA 2004; 101: 7100-7105.
37. Park SW, Moon YA, Horton JD,. Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver. J Biol Chem 2004; 279: 50630-50638.
38. Ishibashi S, Herz J, Maeda N, et al., The two-receptor model of lipoprotein clearance: tests of the hypothesis in 'knockout' mice lacking the low density lipoprotein receptor, apolipoprotein E, or both proteins. Proc Natl Acad Sci USA 1994; 91: 4431-4435.
39. Wang C, Yu X, Cao Q, et al., Characterization of murine macrophages from bone marrow, spleen and peritoneum. BMC Immunol 2013; 14: 6.
40. Chistiakov DA, Bobryshev YV, Nikiforov NG, et al., Macrophage phenotypic plasticity in atherosclerosis: the associated features and the peculiarities of the expression of inflammatory genes. Int J Cardiol 2015; 184C: 436-445.
41. Mallat Z., Macrophages. Arterioscler Thromb Vasc Biol 2014; 34: 2509-2519.
42. Guo J, Bot I, de Nooijer R, et al., Leucocyte cathepsin K affects atherosclerotic lesion composition and bone mineral density in low-density lipoprotein receptor deficient mice. Cardiovasc Res 2009; 81: 278-285.
43. Shah PK,. Inflammation and plaque vulnerability. Cardiovasc Drugs Ther 2009; 23: 31-40.
44. Swirski FK, Nahrendorf M, Etzrodt M, et al., Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science 2009; 325: 612-616.
45. Tacke F, Alvarez D, Kaplan TJ, et al., Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J Clin Invest 2007; 117: 185-194.
46. Ruan XZ, Moorhead JF, Tao JL, et al., Mechanisms of dysregulation of low-density lipoprotein receptor expression in vascular smooth muscle cells by inflammatory cytokines. Arterioscler Thromb Vasc Biol 2006; 26: 1150-1155.
47. Ma KL, Liu J, Wang CX, et al., Activation of mTOR modulates SREBP-2 to induce foam cell formation through increased retinoblastoma protein phosphorylation. Cardiovasc Res 2013; 100: 450-460.
48. Parameswaran N, Patial S,. Tumor necrosis factor-α signaling in macrophages. Crit Rev Eukaryot Gene Expr 2010; 20: 87-103.
49. Stewart CR, Stuart LM, Wilkinson K, et al., CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol 2010; 11: 155-161.
50. Walley KR, Thain KR, Russell JA, et al., PCSK9 is a critical regulator of the innate immune response and septic shock outcome. Sci Transl Med 2014; 6: 258ra143.
51. Mallat Z, Besnard S, Duriez M, et al., Protective role of interleukin-10 in atherosclerosis. Circ Res 1999; 85: e17-24.