Protein S on the surface of plasma lipoproteins: a potential mechanism for protein S delivery to the atherosclerotic plaques?
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
The anticoagulant protein S (PS) binds phospholipids with very high affinity, but PS interaction with lipoproteins and lipidrich atherosclerotic plaques remains still poorly defined. We investigated PS in plasma lipoproteins and in atherosclerotic plaques from ten patients undergoing endarterectomy. PS was detected by Western blotting after exposure of the necrotic core to liposomes and was found to maintain its ability to bind phosphatidylserine micelles. The amounts of PS bound to low/very low-density lipoproteins in patient’ plasmas were higher and more variable than those detected in healthy subjects. A direct correlation between bound PS and low-density lipoproteins (LDL), plasma levels was found only in patients (r=0.921, p<0.001), thereby leading to hypothesize that the PS-phospholipids binding may increase by oxidative processes of LDL in atherosclerotic patients. The presence of the PS into the necrotic core of atherosclerotic plaques and on the surface of lipoproteins, particularly the atherogenic LDL, suggests a LDL-based delivery of PS to the atherosclerotic plaques and emphasizes the deep link between plasma lipids and coagulation in cardiovascular diseases.
Bentzon JF, Otsuka F, Virmani R, Falk E. Mechanisms of plaque formation and rupture. Circ Res. 2014;114:1852-66. DOI: https://doi.org/10.1161/CIRCRESAHA.114.302721
Webb NR. High-Density Lipoproteins and Serum Amyloid A (SAA). Curr Atheroscler Rep. 2021;23:7. DOI: https://doi.org/10.1007/s11883-020-00901-4
Getz GS, Krishack PA, Reardon CA. Serum amyloid A and atherosclerosis Curr Opin Lipidol. 2016;27:531-5. DOI: https://doi.org/10.1097/MOL.0000000000000331
Hartley A, Haskard D, Khamis R. Oxidized LDL and anti-oxidized LDL antibodies in atherosclerosis - Novel insights and future directions in diagnosis and therapy. Trends Cardiovasc Med. 2019;29:22-6. DOI: https://doi.org/10.1016/j.tcm.2018.05.010
Di Scipio RG, Hermodson MA, Yates SG, Davie EW. A comparison of human prothrombin, factor IX (Christmas factor), factor X (Stuart factor), and protein S. Biochemistry. 1977;16:698-706. DOI: https://doi.org/10.1021/bi00623a022
Gierula M, Ahnström J. Anticoagulant protein S-New insights on interactions and functions. J Thromb Haemost. 2020;18:2801-11. DOI: https://doi.org/10.1111/jth.15025
van der Meer JH, van der Poll T, van 't Veer C. TAM receptors, Gas6, and protein S: roles in inflammation and hemostasis. Blood. 2014;123:2460-9. DOI: https://doi.org/10.1182/blood-2013-09-528752
Liao D, Wang X, Li M, et al. Human protein S inhibits the uptake of AcLDL and expression of SR-A through Mer receptor tyrosine kinase in human macrophages. Blood. 2009;113:165-74. DOI: https://doi.org/10.1182/blood-2008-05-158048
Hurtado B, Muñoz X, Recarte-Pelz P, et al. Expression of the vitamin K-dependent proteins GAS6 and protein S and the TAM receptor tyrosine kinases in human atherosclerotic carotid plaques. Thromb Haemost. 2011;105:873-82. DOI: https://doi.org/10.1160/TH10-10-0630
Anderson HA, Maylock CA, Williams JA, et al. Serum-derived protein S binds to phosphatidylserine and stimulates the phagocytosis of apoptotic cells Nat Immunol. 2003;4:87-91. DOI: https://doi.org/10.1038/ni871
Gasic GP, Arenas CP, Gasic TB, Gasic GJ. Coagulation factors X, Xa, and protein S as potent mitogens of cultured aortic smooth muscle cells. Proc Natl Acad Sci U S A. 1992;89:2317-20. DOI: https://doi.org/10.1073/pnas.89.6.2317
Baroni M, Pavani G, Marescotti D, et al. Membrane binding and anticoagulant properties of protein S natural variants. Thromb Res. 2010;125:e33-9. DOI: https://doi.org/10.1016/j.thromres.2009.09.015
Marchetti G, Girelli D, Zerbinati C, et al. An integrated genomic-transcriptomic approach supports a role for the proto-oncogene BCL3 in atherosclerosis. Thromb Haemost. 2015;113:655-63. DOI: https://doi.org/10.1160/TH14-05-0466
Ziliotto N, Meneghetti S, Menegatti E, et al. Expression profiles of the internal jugular and saphenous veins: Focus on hemostasis genes. Thromb Res. 2020;191:113-24. DOI: https://doi.org/10.1016/j.thromres.2020.04.039
Wang Y, Qiao M, Mieyal JJ, et al. Molecular mechanism of glutathione-mediated protection from oxidized low-density lipoprotein-induced cell injury in human macrophages: role of glutathione reductase and glutaredoxin. Free Radic Biol Med. 2006;41:775-85. DOI: https://doi.org/10.1016/j.freeradbiomed.2006.05.029
Baroni M, Mazzola G, Kaabache T, et al. Molecular bases of type II protein S deficiency: the I203-D204 deletion in the EGF4 domain alters GLA domain function. J Thromb Haemost. 2006;4:186-91. DOI: https://doi.org/10.1111/j.1538-7836.2005.01682.x
Steinberg D, Witztum JL. Oxidized low-density lipoprotein and atherosclerosis. Arterioscler Thromb Vasc Biol 2010;30:2311-6. DOI: https://doi.org/10.1161/ATVBAHA.108.179697
Pryma CS, Ortega C, Dubland JA, Francis GA. Pathways of smooth muscle foam cell formation in atherosclerosis. Curr Opin Lipidol. 2019;30:117-24. DOI: https://doi.org/10.1097/MOL.0000000000000574
Benzakour O, Kanthou C. The anticoagulant factor, protein S, is produced by cultured human vascular smooth muscle cells and its expression is up-regulated by thrombin. Blood. 2000;95:2008-14. DOI: https://doi.org/10.1182/blood.V95.6.2008
Martinelli N, Baroni M, Castagna A, et al. Apolipoprotein C-III Strongly Correlates with Activated Factor VII-Anti-Thrombin Complex: An Additional Link between Plasma Lipids and Coagulation. Thromb Haemost. 2019;119:192-202. DOI: https://doi.org/10.1055/s-0038-1676817
Supporting AgenciesThe study has been carried out at the Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy. The study was financially supported by Grant from Italian Ministry of University and Research, University of Ferrara, Italy (FAR 2020, FAR 2021), 5X1000 University of Ferrara grant (2021_NAZ.A_B) and by “Bando FIRD 2022 – BARONI” University of Ferrara grant.
Copyright (c) 2022 The Author(s)
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
PAGEPress has chosen to apply the Creative Commons Attribution NonCommercial 4.0 International License (CC BY-NC 4.0) to all manuscripts to be published.