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Updated: Aug 14, 2026
A Familial Hypercholesterolemia Human Liver Chimeric Mouse Model Using Induced Pluripotent Stem Cell-derived Hepatocytes
Published on: September 15, 2018
PI3KC2α inhibition is antithrombotic in blood from hypercholesterolemic mice
Natasha M Setiabakti1, Volga Tarlac1, Pia Larsson1
1Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria, Australia.
Background:
Current 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.
Objectives:
This study aimed to examine whether genetic deficiency or pharmacologic inhibition of PI3KC2α provides antithrombotic effects in blood from hypercholesterolemic mice.
Methods:
Hypercholesterolemic 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.
Results:
ApoE-/- 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.
Conclusion:
These 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.
