PI3KC2 inhibition is antithrombotic in blood from hypercholesterolemic mice

Background: Current antiplatelet agents exhibit reduced antithrombotic efficacy in high -risk populations such as populations with hypercholesterolemia. The class II PI3kinase, PI3KC2 alpha, is a recently discovered target for novel antiplatelet therapy. PI3KC2 alpha inhibition is antithrombotic in healthy mouse models, but whether this is preserved in hypercholesterolemia remains unknown. Objectives: This study aimed to examine whether genetic deficiency or pharmacologic inhibition of PI3KC2 alpha provides antithrombotic effects in blood from hypercholesterolemic mice. Methods: Hypercholesterolemic PI3KC2 alpha-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 PI3KC2 alpha was examined in whole blood from ApoE-/- mice treated with the PI3KC2 alpha inhibitor MIPS-21335. Results: ApoE-/- mice exhibited the anticipated prothrombotic effect of hypercholesterolemia, with a 1.5 -fold increase in thrombus volume in blood from ApoE-/- vs wildtype mice. This prothrombotic phenotype in blood from hypercholesterolemic mice was significantly reduced with PI3KC2 alpha deficiency. Acute pharmacologic inhibition of PI3KC2 alpha with MIPS-21335 similarly reduced thrombosis in blood from ApoE-/- mice. Conclusion: These findings demonstrate that targeting PI3KC2 alpha results in a potent antithrombotic effect in hypercholesterolemic mice and suggest that PI3KC2 alpha is a promising target for antithrombotic therapy in patients with hypercholesterolemia at a high risk of thrombotic events.