The role of P2Y12 in cardiovascular disease beyond atherothrombosis: P2Y12 signaling promotes emergency hematopoiesis after myocardial infarction

Abstract Background Adenosine diphosphate (ADP) plays a pivotal role in platelet activation. The purinergic ADP-receptor P2Y12 has therefore been targeted the treatment of cardiovascular disease (CVD) to prevent atherothrombosis (1). Beyond expression on platelets, receptors have also described hematopoietic stem and progenitor cells (LSK) (2). After myocardial infarction (MI), accelerated LSK proliferation launches emergency hematopoiesis as driving force behind inflammatory response MI, increasing cell production bone marrow (BM) providing leukocyte resupply for local recruitment infarct (3). cascade after MI covers intricate multilayered interactions between injured myocardium BM that still remain be fully elucidated may unearth novel therapeutic strategies. Whereas P2X recently found involved trafficking (4), P2Y not yet characterized. Purpose This study aims characterize influence signaling cardiac remodeling MI. Methods Permanent coronary ligation was performed assess activation, composition, function murine global platelet-specific knockout models under pharmacological inhibition with prasugrel using flow cytometry, qPCR, immunohistochemistry echocardiography. In vitro studies including colony forming unit (CFU) assays cytometry allowed investigation ADP-dependent effects intracellular pathway analysis. Results We identified ADP danger signal BM, fueling by promoting Akt phosphorylation cycle progression. Detection implicated direct effect via signaling. deficiency decelerated consecutively reduced excessive translating lower numbers progenitors blood infarct. Ultimately, ameliorated chronic adverse preserved Conclusion P2Y12-mediated activation promotes fuels post-ischemic inflammation, proposing antagonists CVD beyond atherothrombosis. Funding Acknowledgement Type funding sources: Public grant(s) – National budget only. Main source(s): Deutsche Forschungsgemeinschaft (DFG)