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Total body proteoglycan 4 (Prg4) deficiency increases atherosclerosis susceptibility in apolipoprotein E knockout and low-density lipoprotein receptor knockout mice

2018; Elsevier BV; Volume: 278; Linguagem: Inglês

10.1016/j.atherosclerosis.2018.06.883

1879-1484

Joya E. Nahon, Menno Hoekstra, Miranda Van Eck,

Protease and Inhibitor Mechanisms

Proteoglycan 4 (Prg4) is a mediator in inflammatory processes, either directly through interactions with CD44 [ [1] Al-Sharif A. Jamal M. Zhang L.X. Larson K. Schmidt T.A. Jay G.D. Elsaid K.A. Lubricin/proteoglycan 4 binding to CD44 receptor: a mechanism of the suppression of proinflammatory cytokine-induced synoviocyte proliferation by lubricin. Arthritis Rheum. 2015; 67: 1503-1513https://doi.org/10.1002/art.39087 Crossref PubMed Scopus (78) Google Scholar ] or toll-like receptors [ [2] Alquraini A. Garguilo S. Souza G.D. Zhang L.X. Schmidt T.A. Jay G.D. Elsaid K.A. The interaction of lubricin/proteoglycan 4 ( PRG4 ) with toll-like receptors 2 and 4 : an anti-inflammatory role of PRG4 in synovial fluid. Arthritis Res. Ther. 2015; : 1-12https://doi.org/10.1186/s13075-015-0877-x Crossref PubMed Scopus (72) Google Scholar ], or indirectly as a growth factor for hematopoietic cell lineages [ [3] Liu Y.J. Lu S.H. Xu B. Yang R.C. Ren Q. Liu B. Li B. Lu M. Yan F.Y. Han Z.B. Han Z.C. Hemangiopoietin, a novel human growth factor for the primitive cells of both hematopoietic and endothelial cell lineages. Blood. 2004; 103: 4449-4456https://doi.org/10.1182/blood-2003-06-1825 Crossref PubMed Scopus (58) Google Scholar ]. In line with this, in our article "Proteoglycan 4 regulates macrophage function without altering atherosclerotic lesion formation in a murine bone marrow-specific deletion model" published in Atherosclerosis, we showed that Prg4 deficiency attenuated the LPS-induced pro-inflammatory response in macrophages [ [4] Nahon J.E. Hoekstra M. Havik S.R. Van Santbrink P.J. Dallinga-Thie G.M. Kuivenhoven J.A. Geerling J.J. Van Eck M. Proteoglycan 4 regulates macrophage function without altering atherosclerotic lesion formation in a murine bone marrow-specific deletion model. Atherosclerosis. 2018; 274: 120-127https://doi.org/10.1016/j.atherosclerosis.2018.05.008 Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar ]. However, to our surprise, bone marrow-specific Prg4 deficiency did not affect atherosclerotic lesion development in mice [ [4] Nahon J.E. Hoekstra M. Havik S.R. Van Santbrink P.J. Dallinga-Thie G.M. Kuivenhoven J.A. Geerling J.J. Van Eck M. Proteoglycan 4 regulates macrophage function without altering atherosclerotic lesion formation in a murine bone marrow-specific deletion model. Atherosclerosis. 2018; 274: 120-127https://doi.org/10.1016/j.atherosclerosis.2018.05.008 Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar ]. Given that Prg4 is an ubiquitously expressed and secreted proteoglycan, we anticipated that the quantitative contribution of bone marrow-derived Prg4 to the total serum Prg4 levels is minimal [ [4] Nahon J.E. Hoekstra M. Havik S.R. Van Santbrink P.J. Dallinga-Thie G.M. Kuivenhoven J.A. Geerling J.J. Van Eck M. Proteoglycan 4 regulates macrophage function without altering atherosclerotic lesion formation in a murine bone marrow-specific deletion model. Atherosclerosis. 2018; 274: 120-127https://doi.org/10.1016/j.atherosclerosis.2018.05.008 Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar ]. This led us to the hypothesis that the overall availability of Prg4 in the serum rather than the source of Prg4 production is the determining factor in atherosclerotic lesion formation. Therefore, we aimed to establish whether total body Prg4 deficiency affects atherosclerosis susceptibility. Hereto, two commonly used hyperlipidemic mouse models for atherosclerosis were used, namely apolipoprotein E knockout (ApoE KO) mice and low-density lipoprotein receptor knockout (Ldlr KO) mice. Proteoglycan 4 regulates macrophage function without altering atherosclerotic lesion formation in a murine bone marrow-specific deletion modelAtherosclerosisVol. 274PreviewProteoglycan 4 (Prg4) has a high structural similarity with the established atherosclerosis-modulating proteoglycan versican, but its role in atherogenesis is still unknown. Therefore, the impact of Prg4 deficiency on macrophage function in vitro and atherosclerosis susceptibility in vivo was investigated. Full-Text PDF