title: Role of protein kinase CK2 in the dynamic interaction of platelets, leukocytes and endothelial cells during thrombus formation.
abstract: BACKGROUND
  Thrombus formation is a complex process, which is characterized by the dynamic interaction of platelets, leukocytes and endothelial cells. The activation of these cells is strictly mediated by different phospho-regulated signaling pathways. Recently, it has been reported that inhibition of protein kinase CK2 affects platelet function by suppressing phosphatidylinositol-4,5-bisphosphate-3-kinase (PI3K) signaling. Based on this finding, we herein analyzed whether CK2 acts as a crucial regulator of thrombus formation.
  
  
  METHODS
  We examined the effect of CK2 inhibition on platelet activation and aggregation, the formation of platelet-leukocyte aggregates (PLA), the endothelial expression of von Willebrand factor (vWF), intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1, and the subcellular localization of nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) and phospho-p65 in human dermal microvascular endothelial cells (HDMEC). Dorsal skinfold chambers were prepared in BALB/c mice to analyze in vivo the effect of CK2 inhibition on photochemically induced thrombus formation using intravital fluorescence microscopy.
  
  
  RESULTS
  CK2 inhibition by CX-4945 suppressed adenosin diphosphate (ADP)- and proteinase-activated receptor-1-peptide (PAR-1-AP)-stimulated platelet aggregation, which was associated with down-regulation of P-selectin, GPIIb/IIIa and a reduced formation of PLA. Expression and secretion of vWF was diminished in CX-4945-treated HDMEC. Moreover, CK2 inhibition attenuated the endothelial expression of VCAM-1, whereas the expression of ICAM-1 was not affected. Finally, CX-4945-treated mice exhibited a significantly delayed photochemically induced thrombus formation when compared to vehicle-treated controls.
  
  
  CONCLUSIONS
  These results indicate that CK2 is a pleiotropic regulator of thrombus formation, affecting multiple interactions of platelets, leukocytes and endothelial cells.
authors.affiliation: Institute for Clinical & Experimental Surgery, Saarland University, 66421 Homburg/Saar, Germany. Electronic address: emmanuel.ampofo@uks.eu.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Ampofo
authors.affiliation: Institute of Clinical Hemostaseology & Transfusion Medicine, 66421 Homburg/Saar, Germany.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Müller
authors.affiliation: Institute for Clinical & Experimental Surgery, Saarland University, 66421 Homburg/Saar, Germany.
authors.forename: Indra N
authors.initials: IN
authors.lastname: Dahmke
authors.affiliation: Institute of Clinical Hemostaseology & Transfusion Medicine, 66421 Homburg/Saar, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Eichler
authors.affiliation: Medical Biochemistry and Molecular Biology, Saarland University, 66421 Homburg/Saar, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Montenarh
authors.affiliation: Institute for Clinical & Experimental Surgery, Saarland University, 66421 Homburg/Saar, Germany.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Menger
authors.affiliation: Institute for Clinical & Experimental Surgery, Saarland University, 66421 Homburg/Saar, Germany.
authors.forename: Matthias W
authors.initials: MW
authors.lastname: Laschke
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000201:enzymology* / Q000473:pathology; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000097:blood*; D002450:Cell Communication / Q000502:physiology*; D042783:Endothelial Cells / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D007962:Leukocytes / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D013927:Thrombosis / Q000201:enzymology* / Q000473:pathology
chemical_list: D047428:Protein Kinase Inhibitors; D047390:Casein Kinase II
keywords: CK2; Dorsal skinfold chamber; Endothelial cells; Leukocytes; Platelets; Thrombosis