title: Suppression of proatherogenic leukocyte interactions by MCS-18--Impact on advanced atherosclerosis in ApoE-deficient mice.
abstract: OBJECTIVE
  Atherosclerosis is associated with chronic inflammatory responses of the arterial blood vessels. The previously observed protective effect of the MCS-18 substance against the initiation of atherosclerosis in a murine model was explained by its pronounced anti-inflammatory activity. Here, we investigated its impact on murine plaque progression in advanced atherosclerosis and on proatherogenic processes.
  
  
  RESULTS
  ApoE-deficient mice were fed a high-fat diet for 12 weeks to induce atherosclerosis, followed by normal chow and intraperitoneal injections of either MCS-18 (500 μg, n = 10) or saline (n = 10) twice a week for another 12 weeks. Plaque size was reduced in MCS-18 treated mice compared to controls (p = 0.001), which was associated with a reduced size of the lipid core (p = 0.01). There was a decrease in apoptotic cells (p = 0.02), endothelial ICAM-1 expression (p < 0.001), and macrophage density (p = 0.01) in the MCS-18 group. In addition, human and murine dendritic cells (DCs) and human umbilical vein endothelial cells (HUVECs) were treated with MCS-18 (50-200 μg/ml) to analyze cell migration and adhesion under flow conditions. MCS-18 reduced human (p = 0.01) and murine (p = 0.006) DC migration. Furthermore, adhesion of MCS-18-treated DCs to a HUVEC monolayer was decreased (p < 0.001). Compared to controls, CD209 (p < 0.001) and CCR7 (p = 0.003) expression was decreased in MCS-18-treated DCs, while in HUVECs lower levels of ICAM-1 (p < 0.001) and of phosphorylated NF-κB-p65 (p = 0.002) were observed. Blocking of ICAM-1 reduced DC adhesion (p < 0.001).
  
  
  CONCLUSIONS
  MCS-18 exhibits interesting therapeutic effects when applied in advanced murine atherosclerosis. Its antiatherogenic impact might be associated with a suppressed adhesion to the endothelium due to down-regulation of endothelial ICAM-1 expression.
authors.affiliation: Department of Cardiology and Angiology, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, Germany.
authors.forename: Constanze
authors.initials: C
authors.lastname: Kuehn
authors.affiliation: Department of Cardiology and Angiology, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, Germany.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Tauchi
authors.affiliation: Department of Cardiology and Angiology, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Stumpf
authors.affiliation: Department of Nephropathology, FAU Erlangen-Nürnberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Daniel
authors.affiliation: Department of Radiology, FAU Erlangen-Nürnberg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Bäuerle
authors.affiliation: Department of Radiology, FAU Erlangen-Nürnberg, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Schwarz
authors.affiliation: DoNatur GmbH, Martinsried, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Kerek
authors.affiliation: Department of Immune Modulation, FAU Erlangen-Nürnberg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Steinkasserer
authors.affiliation: Department of Immune Modulation, FAU Erlangen-Nürnberg, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Zinser
authors.affiliation: Department of Cardiology and Angiology, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Achenbach
authors.affiliation: Department of Cardiology and Angiology, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, Germany. Electronic address: Barbara.Dietel@uk-erlangen.de.
authors.forename: Barbara
authors.initials: B
authors.lastname: Dietel
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D001688:Biological Products / Q000494:pharmacology*; D004195:Disease Models, Animal; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics*; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics
chemical_list: D001057:Apolipoproteins E; D001688:Biological Products; C534850:MCS-18; D016328:NF-kappa B; D018799:Intercellular Adhesion Molecule-1
keywords: Adhesion; ApoE-deficient mice; Atherosclerosis; Dendritic cells; HUVEC; Inflammation; MCS-18