PI3KC2α inhibition is antithrombotic in blood from hypercholesterolemic mice

Abstract

BackgroundCurrent antiplatelet agents exhibit reduced antithrombotic efficacy in high-risk populations such as populations with hypercholesterolemia. The class II PI3-kinase, PI3KC2α, is a recently discovered target for novel antiplatelet therapy. PI3KC2α inhibition is antithrombotic in healthy mouse models, but whether this is preserved in hypercholesterolemia remains unknown. ObjectivesThis study aimed to examine whether genetic deficiency or pharmacologic inhibition of PI3KC2α provides antithrombotic effects in blood from hypercholesterolemic mice. MethodsHypercholesterolemic PI3KC2α-deficient mice were generated by breeding into an ApoE−/− background. Thrombosis was examined using an ex vivo whole blood thrombosis assay. The effect of pharmacologic inhibition of PI3KC2α was examined in whole blood from ApoE−/− mice treated with the PI3KC2α inhibitor MIPS-21335. ResultsApoE−/− mice exhibited the anticipated prothrombotic effect of hypercholesterolemia, with a 1.5-fold increase in thrombus volume in blood from ApoE−/− vs wild-type mice. This prothrombotic phenotype in blood from hypercholesterolemic mice was significantly reduced with PI3KC2α deficiency. Acute pharmacologic inhibition of PI3KC2α with MIPS-21335 similarly reduced thrombosis in blood from ApoE−/− mice. ConclusionThese findings demonstrate that targeting PI3KC2α results in a potent antithrombotic effect in hypercholesterolemic mice and suggest that PI3KC2α is a promising target for antithrombotic therapy in patients with hypercholesterolemia at a high risk of thrombotic events.