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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.
Insights
Targeting PI3-kinase catalytic subunit type 2 alpha (PI3KC2α) reduces blood clot formation in hypercholesterolemic mice. This suggests PI3KC2α inhibition is a promising strategy for preventing thrombotic events in high-risk patients.
Area of Science:
- Biochemistry
- Pharmacology
- Cardiovascular Research
Background:
- Current antiplatelet therapies show limited efficacy in hypercholesterolemic patients.
- Phosphatidylinositol 3-kinase catalytic subunit type 2 alpha (PI3KC2α) is a novel target for antiplatelet interventions.
- PI3KC2α inhibition's antithrombotic effect in hypercholesterolemia is not well-established.
Purpose of the Study:
- To investigate the antithrombotic potential of PI3KC2α deficiency or inhibition in hypercholesterolemic mouse models.
- To assess the efficacy of targeting PI3KC2α in reducing thrombosis associated with hypercholesterolemia.
Main Methods:
- Generated hypercholesterolemic PI3KC2α-deficient mice by breeding into an ApoE-/- background.
- Utilized an ex vivo whole blood assay to measure thrombosis.
- Administered a PI3KC2α inhibitor (MIPS-21335) to ApoE-/- mice to assess pharmacologic inhibition.
Main Results:
- ApoE-/- mice exhibited a 1.5-fold increase in thrombus volume, confirming a prothrombotic state.
- PI3KC2α deficiency significantly reduced the prothrombotic phenotype in hypercholesterolemic mice.
- Pharmacologic inhibition of PI3KC2α with MIPS-21335 also decreased thrombosis in hypercholesterolemic mouse blood.
Conclusions:
- Targeting PI3KC2α demonstrates potent antithrombotic effects in hypercholesterolemic mice.
- PI3KC2α inhibition represents a promising therapeutic strategy for patients with hypercholesterolemia.
- This approach may reduce the risk of thrombotic events in high-risk populations.
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.
