title: Deficiency of the TLR4 analogue RP105 aggravates vein graft disease by inducing a pro-inflammatory response.
abstract: Venous grafts are often used to bypass occlusive atherosclerotic lesions; however, poor patency leads to vein graft disease. Deficiency of TLR4, an inflammatory regulator, reduces vein graft disease. Here, we investigate the effects of the accessory molecule and TLR4 analogue RadioProtective 105 (RP105) on vein graft disease. RP105 deficiency resulted in a 90% increase in vein graft lesion area compared to controls. In a hypercholesterolemic setting (LDLr(-/-)/RP105(-/-) versus LDLr(-/-) mice), which is of importance as vein graft disease is usually characterized by excessive atherosclerosis, total lesion area was not affected. However we did observe an increased number of unstable lesions and intraplaque hemorrhage upon RP105 deficiency. In both setups, lesional macrophage content, and lesional CCL2 was increased. In vitro, RP105(-/-) smooth muscle cells and mast cells secreted higher levels of CCL2. In conclusion, aggravated vein graft disease caused by RP105 deficiency results from an increased local inflammatory response.
authors.affiliation: Division of Biopharmaceutics, LACDR, Leiden University, Leiden, The Netherlands.|Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Anouk
authors.initials: A
authors.lastname: Wezel
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.|Einthoven Laboratory for Experimental Vascular Medicine, Leiden, The Netherlands.
authors.forename: Margreet R
authors.initials: MR
authors.lastname: de Vries
authors.affiliation: Division of Biopharmaceutics, LACDR, Leiden University, Leiden, The Netherlands.
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Maassen
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Kip
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.|Einthoven Laboratory for Experimental Vascular Medicine, Leiden, The Netherlands.
authors.forename: Erna A
authors.initials: EA
authors.lastname: Peters
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.|Einthoven Laboratory for Experimental Vascular Medicine, Leiden, The Netherlands.
authors.forename: Jacco C
authors.initials: JC
authors.lastname: Karper
authors.affiliation: Division of Biopharmaceutics, LACDR, Leiden University, Leiden, The Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: Kuiper
authors.affiliation: Division of Biopharmaceutics, LACDR, Leiden University, Leiden, The Netherlands.|Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Ilze
authors.initials: I
authors.lastname: Bot
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.|Einthoven Laboratory for Experimental Vascular Medicine, Leiden, The Netherlands.
authors.forename: Paul H A
authors.initials: PHA
authors.lastname: Quax
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism*; D015870:Gene Expression; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008407:Mast Cells / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D018836:Inflammation Mediators; C490500:Ly78 protein, mouse; D011973:Receptors, LDL; D019714:Tissue Inhibitor of Metalloproteinases; D020782:Matrix Metalloproteinases