OC 78.2 - Platelet-specific deletion of CK2α results in a robust protection against arterial thrombosis and beneficial myocardial recovery after I/R injury

Background: Cardiovascular diseases depend on platelet functions such as adhesion, secretion and thrombus formation. Since the activation of platelets is regulated by many intracellular, phosphorylation-dependent signaling cascades, highly expressed kinases in platelets play a pivotal role in platelet activation. One of them is the casein kinase 2 (CK2), which consists of two regulatory β and two catalytic α or α’ subunits respectively. While deficiency of the regulatory β subunit is characterized by impaired thrombopoiesis and platelet function, nothing is yet known about the role of the α subunit in platelet activation, in vivo thrombus formation and myocardial recovery after ischemia/reperfusion (I/R) injury.

Aims: The present study examined the effects of CK2α-dependent platelet activation, in vivo thrombus formation and I/R injury.

Methods: With the use of platelet-specific CK2α-deficient mice (csnk2αPf4∆/Pf4∆) and wild-type littermates (csnk2αlox/lox), in vitro studies were used to investigate platelet activation, aggregation and calcium release. Using in vivo models of FeCl3-induced injury and myocardial ischemia/reperfusion injury effects on thrombus formation and myocardial recovery were investigated.

Results: Flow cytometric analysis demonstrated disturbed integrin αIIbβ3 activation and P-selectin surface exposure in csnk2αPf4∆/Pf4∆ platelets upon stimulation with platelet agonist CRP. Spectrofluorimetric measurements detected a significantly decreased intracellular Ca2+ release and extracellular Ca2+ influx after CRP stimulation in CK2α-deficient platelets. In addition, CRP-dependent platelet aggregation and secretion were abrogated in CK2α-deficient platelets. FeCl3-induced injury in carotid and mesenteric arteries in vivo, showed decreased thrombus formation in csnk2αPf4∆/Pf4∆ mice. However, in a tail tip transection model remarkably no difference between bleeding times was found, although csnk2α-deficient mice displayed a decreased infarct size and improved cardiac function after myocardial ischemia/reperfusion injury.

Conclusion(s): The present study discloses CK2α as crucial regulator of platelet activation, arterial thrombus formation and myocardial revovery. Concluding, CK2α could therefore represent a promising new pharmacological target.