casein-kinase-ii and Thrombosis

Thrombus formation is dependent on the interaction of platelets, leukocytes and endothelial cells as well as proteins of the coagulation cascade. This interaction is tightly controlled by phospho-regulated pathways involving protein kinase CK2. A growing number of studies have demonstrated an important role of this kinase in the regulation of primary and secondary hemostasis. Inhibition of CK2 downregulates the expression of important adhesion molecules on platelets and endothelial cells, such as glycoprotein (GP)IIb/IIIa, P-selectin, von Willebrand factor and vascular cell adhesion molecule. Moreover, the reduced CK2-dependent phosphorylation of different coagulation factors prevents the conversion of fibrinogen to fibrin. Targeting these mechanisms may open the door for the development of novel anti-thrombotic therapies.

Topics: Casein Kinase II; Endothelial Cells; Humans; Leukocytes; Thrombosis

Platelets, anucleated megakaryocyte (MK)-derived cells, play a major role in hemostasis and arterial thrombosis. Although protein kinase casein kinase 2 (CK2) is readily detected in MKs and platelets, the impact of CK2-dependent signaling on MK/platelet (patho-)physiology has remained elusive. The present study explored the impact of the CK2 regulatory β-subunit on platelet biogenesis and activation. MK/platelet-specific genetic deletion of CK2β (

Topics: Animals; Blood Platelets; Calcium Signaling; Casein Kinase II; Megakaryocytes; Mice; Mice, Knockout; Peptide Fragments; Platelet Activation; Thrombopoiesis; Thrombosis

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.. 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.. 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.. These results indicate that CK2 is a pleiotropic regulator of thrombus formation, affecting multiple interactions of platelets, leukocytes and endothelial cells.

Topics: Animals; Blood Platelets; Casein Kinase II; Cell Communication; Endothelial Cells; Humans; Leukocytes; Mice; Mice, Inbred BALB C; Protein Kinase Inhibitors; Thrombosis