Platelet Casein Kinase 2α is a pivotal player in arterial thrombotic occlusion and post-ischemic myocardial remodeling

AIMS: Platelets play a major role in thrombo-inflammatory cardiovascular diseases such as myocardial infarction. Although platelet function is crucially determined by kinases, the impact of Casein Kinase 2α (CK2α) on platelet activation during arterial thrombosis and myocardial remodeling following ischemia and reperfusion (I/R) injury is not known. METHODS AND RESULTS: Using platelet-specific deletion of Csnk2a1 in mice, the evaluation of the CK2α-dependent platelet phosphoproteome revealed a diminished phosphorylation of the IP3 receptor type-1 in Csnk2a1-deficient mice. This finding was accompanied by attenuated IP3-induced Ca2+ mobilization, impaired integrin αIIbβ3 activation, abrogated platelet aggregation and secretion, as well as defective spreading on fibrinogen in response to collagen-related peptide. Accordingly, without affecting primary hemostasis, thrombotic vascular occlusion in vivo was diminished in Csnk2a1-deficient mice. When subjected to a myocardial I/R injury model, these mice displayed improved cardiac outcome when compared with wildtype mice. Raman spectromics, spatial metabolomics and molecular approaches revealed locally a CK2α-dependent release of chondroitin sulfate and transforming growth factor-β from platelets, which was associated with significantly reduced ventricular fibrosis and improved heart function in Csnk2a1-deficient mice. CONCLUSION: Altogether, our results disclose CK2α as pivotal player in platelet activation and pathogenesis of post-ischemic myocardial remodeling, including myocardial fibrosis and left ventricular impairment following myocardial ischemia.