Elimination of platelet factor 4 (PF4) from platelets reduces atherosclerosis in C57Bl/6 and apoE-/- mice

Bruce S. Sachais; Tiffany Turrentine; Jennine M. Dawicki McKenna; Ann H. Rux; Daniel Rader; Anna M. Kowalska

doi:10.1160/TH07-04-0271

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2007; 98(05): 1108-1113
DOI: 10.1160/TH07-04-0271

Cardiovascular Biology and Cell Signalling

Schattauer GmbH

Elimination of platelet factor 4 (PF4) from platelets reduces atherosclerosis in C57Bl/6 and apoE^-/- mice

Authors

Bruce S. Sachais

¹Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
Tiffany Turrentine

¹Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
Jennine M. Dawicki McKenna

¹Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
Ann H. Rux

¹Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
Daniel Rader

²Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
Anna M. Kowalska

³Department of Hematology, Children’s Hospital of Philadelphia; Philadelphia, Pennsylvania, USA

⁴Center for Medical Biology, Lodz, Poland

Abstract

Summary

Activated platelets, which release platelet factor 4 (PF4) are present in patients with atherosclerosis. To date, no direct invivo evidence exists for the involvement of PF4 in atherogenesis. In the current study, we tested the hypothesis that PF4 is atherogenic, and that genetic elimination of PF4 would protect mice from atherosclerosis. We have bred PF4^-/- mice onto two athero-susceptible backgrounds, WT-C57Bl/6(WT) and apoE^-/- to examine the importance of PF4 in atherogenesis. In order to induce atherosclerosis, WT and PF4^-/- mice were fed an atherogenic diet for 30 weeks, while apoE^-/- and apoE^-/- PF4^-/- mice were fed a high-fat Western-style diet for 10 weeks. Examination of lesions in the aortic roots of atherogenic diet fed mice demonstrated reduced atherosclerosis in PF4^-/- (20% compared to WT). Examination of apoE^-/- mice demonstrated similar changes, with apoE^-/- PF4^-/- mice demonstrating 37% of the aortic atherosclerotic burden compared to apoE^-/- mice. Although we found similar levels of total and non-HDL cholesterol inWT and PF4^-/- mice, HDL-cholesterol levels were increased in PF4^-/- on both backgrounds. These data demonstrate, for the first time, that the platelet specific chemokine PF4 promotes atherosclerotic lesion development in vivo.

Keywords

Platelets - platelet factor 4 (PF4) - chemokines - atherosclerosis

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Referenzen

References
1 Massberg S, Brand K, Gruner S. et al. A critical role of platelet adhesion in the initiation of atherosclerotic lesion formation. J Exp Med 2002; 196: 887-896.
2 Huo Y, Schober A, Forlow SB. et al. Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E. Nat Med 2003; 9: 61-67.
3 Holm T, Damas JK, Holven K. et al. CXC-chemokines in coronary artery disease: possible pathogenic role of interactions between oxidized low-density lipoprotein, platelets and peripheral blood mononuclear cells. J Thromb Haemost 2003; 1: 257-262.
4 Fateh-Moghadam S, Li ZY, Ersel S. et al. Platelet degranulation is associated with progression of intimamedia thickness of the common carotid artery in patients with diabetes mellitus type 2. Arterioscler Thromb Vasc Biol 2005; 25: 1299-1303.
5 Gawaz M. Platelets in the onset of atherosclerosis. Blood Cells Mol Dis 2006; 36: 206-210.
6 Pitsilos S, Hunt JL, Mohler 3rd ER. et al. Platelet factor 4 localization in carotid atherosclerotic plaques: Correlation with clinical parameters. Thromb Haemost 2003; 90: 1142-1150.
7 O’Brien JR, Etherington MD, Pashley M. Intra-platelet platelet factor 4 (IP.PF4) and the heparin-mobilisable pool of PF4 in health and atherosclerosis. Thromb Haemost 1984; 51: 354-357.
8 Sevitt S. Platelets and foam cells in the evolution of atherosclerosis. Histological and immunohistological studies of human lesions. Atherosclerosis 1986; 61: 107-115.
9 Chesterman CN, Berndt MC. Platelet and vessel wall interaction and the genesis of atherosclerosis. Clin Haematol 1986; 15: 323-353.
10 Johnson RC, Chapman SM, Dong ZM. et al. Absence of P-selectin delays fatty streak formation in mice. J Clin Invest 1997; 99: 1037-1043.
11 Manka D, Collins RG, Ley K. et al. Absence of p-selectin, but not intercellular adhesion molecule-1, attenuates neointimal growth after arterial injury in apolipoprotein e-deficient mice. Circulation 2001; 103: 1000-1005.
12 Collins RG, Velji R, Guevara NV. et al. P-Selectin or intercellular adhesion molecule (ICAM)-1 deficiency substantially protects against atherosclerosis in apolipoprotein E-deficient mice. J Exp Med 2000; 191: 189-194.
13 Burger PC, Wagner DD. Platelet P-selectin facilitates atherosclerotic lesion development. Blood 2003; 101: 2661-2666.
14 Rollins JR. Chemokines. Blood 1997; 90: 909-928.
15 Niewiarowski S. Secreted Platelet Products. In: Hemostasis and Thromsosis. London:: Churchill Livingstone;; 1993
16 Busch C, Dawes J, Pepper DS. et al. Binding of platelet factor 4 to cultured human umbilical vein endothelial cells. Thromb Res 1980; 19: 129-137.
17 Loscalzo J, Melnick B, Handin RI. The interaction of platelet factor four and glycosaminoglycans. Arch Biochem Biophys 1985; 240: 446-455.
18 Peterson F, Bock L, Flad HD. et al. A chondroitin sulfate proteoglycan on human neutrophils specifically binds platelet factor 4 and is Involved in cell activation. J Immunol 1998; 161: 4347-4355.
19 Handin RI, Cohen HJ. Purification and binding properties of human platelet factor four. J Biol Chem 1976; 251: 4273-4282.
20 Petersen F, Brandt E, Lindahl U. et al. Characterization of a neutrophil cell surface glycosaminoglycan that mediates binding of platelet factor 4. J Biol Chem 1999; 274: 12376-12382.
21 Rucinski B, Niewiarowski S, Strzyzewski M. et al. Human platelet factor 4 and its C-terminal peptides: heparin binding and clearance from the circulation. Thromb Haemost 1990; 63: 493-498.
22 Sachais BS, Kuo A, Nassar T. et al. Platelet factor 4 binds to low-density lipoprotein receptors and disrupts the endocytic itinerary, resulting in retention of lowdensity lipoprotein on the cell surface. Blood 2002; 99: 3613-3622.
23 Lasagni L, Francalanci M, Annunziato F. et al. An alternatively spliced variant of CXCR3 mediates the inhibition of endothelial cell growth induced by IP-10, Mig, and I-TAC, and acts as functional receptor for platelet factor 4. J Exp Med 2003; 197: 1537-1549.
24 Eslin DE, Zhang C, Samuels KJ. et al. Transgenic mice studies demonstrate a role for platelet factor 4 in thrombosis: dissociation between anticoagulant and antithrombotic effect of heparin. Blood 2004; 104: 3173-3180.
25 Tsukamoto K, Hiester KG, Smith P. et al. Comparison of human apoA-I expression in mouse models of atherosclerosis after gene transfer using a second generation adenovirus. J Lipid Res 1997; 38: 1869-1876.
26 Tangirala RK, Tsukamoto K, Chun SH. et al. Regression of atherosclerosis induced by liver-directed gene transfer of apolipoprotein A-I in mice. Circulation 1999; 100: 1816-1822.
27 Rauova L, Poncz M, McKenzie SE. et al. Ultralarge complexes of PF4 and heparin are central to the pathogenesis of heparin-induced thrombocytopenia. Blood 2005; 105: 131-138.
28 Gewirtz AM, Zhang J, Ratajczak J. et al. Chemokine regulation of human megakaryocytopoiesis. Blood 1995; 86: 2559-2567.
29 Lambert MP, Rauova L, Bailey M. et al. Platelet factor 4 is a negative autocrine in vivo regulator of megakaryopoiesis: clinical and therapeutic implications. Blood 2007; 110: 1153-1160.
30 Rauova L, Zhai L, Kowalska MA. et al. Role of platelet surface PF4 antigenic complexes in heparin-induced thrombocytopenia pathogenesis: diagnostic and therapeutic implications. Blood 2005; 107: 2346-2353.
31 Frenette PS, Johnson RC, Hynes RO. et al. Platelets roll on stimulated endothelium in vivo: an interaction mediated by endothelial P-selectin. Proc Natl Acad Sci USA 1995; 92: 7450-7454.
32 Abi-Younes S, Sauty A, Mach F. et al. The stromal cell-derived factor-1 chemokine is a potent platelet agonist highly expressed in atherosclerotic plaques. Circ Res 2000; 86: 131-138.
33 Gear AR, Suttitanamongkol S, Viisoreanu D. et al. Adenosine diphosphate strongly potentiates the ability of the chemokines MDC, TARC, and SDF-1 to stimulate platelet function. Blood 2001; 97: 937-945.
34 Kowalska MA, Ratajczak MZ, Majka M. et al. Stromal cell-derived factor-1 and macrophage-derived chemokine: 2 chemokines that activate platelets. Blood 2000; 96: 50-57.
35 Kowalska MA, Ratajczak J, Hoxie J. et al. Megakaryocyte precursors, megakaryocytes and platelets express the HIV co-receptor CXCR4 on their surface: determination of response to stromal-derived factor-1 by megakaryocytes and platelets. Br J Haematol 1999; 104: 220-229.
36 Nassar T, Sachais BS, Akkawi S. et al. Platelet factor 4 enhances the binding of oxidized low-density lipoprotein to vascular wall cells. J Biol Chem 2003; 278: 6187-6193.
37 Yu G, Rux AH, Ma P. et al. Endothelial expression of E-selectin is induced by the platelet-specific chemokine platelet factor 4 through LRP in an NF- {kappa}B-dependent manner. Blood 2005; 105: 3545-3551.
38 Scheuerer B, Ernst M, Durrbaum-Landmann I. et al. The CXC-chemokine platelet factor 4 promotes monocyte survival and induces monocyte differentiation into macrophages. Blood 2000; 95: 1158-1166.
39 Deuel TF, Senior RM, Chang D. et al. Platelet factor 4 is chemotactic for neutrophils and monocytes. Proc Natl Acad Sci USA 1981; 78: 4584-4587.
40 Daugherty A, Whitman SC. Quantification of atherosclerosis in mice. Methods Mol Biol 2003; 209: 293-309.
41 Breslow JL. Transgenic mouse models of lipoprotein metabolism and atherosclerosis. Proc Natl Acad Sci USA 1993; 90: 8314-8318.
42 Lusis AJ. The mouse model for atherosclerosis. Trends Cardiovasc Med 1993; 3: 135-143.
43 Rosenfeld ME, Polinsky P, Virmani R. et al. Advanced atherosclerotic lesions in the innominate artery of the ApoE knockout mouse. Arterioscler Thromb Vasc Biol 2000; 20: 2587-2592.
44 Trigatti B, Rayburn H, Vinals M. et al. Influence of the high density lipoprotein receptor SR-BI on reproductive and cardiovascular pathophysiology. Proc Natl Acad Sci USA 1999; 96: 9322-9327.
45 Kozarsky KF, Donahee MH, Glick JM. et al. Gene transfer and hepatic overexpression of the HDL receptor SR-BI reduces atherosclerosis in the cholesterol-fed LDL receptor-deficient mouse. Arterioscler Thromb Vasc Biol 2000; 20: 721-727.
46 Rubin EM, Krauss RM, Spangler EA. et al. Inhibition of early atherogenesis in transgenic mice by human apolipoprotein AI. Nature 1991; 353: 265-267.
47 Plump AS, Scott CJ, Breslow JL. Human apolipoprotein A-I gene expression increases high density lipoprotein and suppresses atherosclerosis in the apolipoprotein E-deficient mouse. Proc Natl Acad Sci USA 1994; 91: 9607-9611.
48 Paszty C, Maeda N, Verstuyft J. et al. Apolipoprotein AI transgene corrects apolipoprotein E deficiencyinduced atherosclerosis in mice. J Clin Invest 1994; 94: 899-903.
49 Nestel P, Fujii A, Allen T. The cis-9,trans-11 isomer of conjugated linoleic acid (CLA) lowers plasma triglyceride and raises HDL cholesterol concentrations but does not suppress aortic atherosclerosis in diabetic apoE-deficient mice. Atherosclerosis 2006; 189: 282-287.
50 Morishima A, Ohkubo N, Maeda N. et al. NF{kappa}B regulates plasma apolipoprotein A-I and high density lipoprotein cholesterol through inhibition of peroxisome proliferator-activated receptor {alpha}. J Biol Chem 2003; 278: 38188-38193.
51 von Hundelshausen P, Koenen RR, Sack M. et al. Heterophilic interactions of platelet factor 4 and RANTES promote monocyte arrest on endothelium. Blood 2005; 105: 924-930.