Key result
LRP5 inhibition attenuates P2Y12 signaling, reducing platelet activation and thrombus formation without significantly increasing bleeding risk.
LRP5 inhibition represents a potential novel therapeutic pathway for reducing thrombosis without the associated bleeding risk seen with traditional antiplatelet agents.
LRP5 interacts with the purinergic ADP receptor P2Y12 on platelets. Upon ADP binding, Gi-coupled P2Y12 activates the PI3K/AKT pathway and inhibits adenylyl cyclase, leading to reduced intracellular cAMP levels. This results in VASP dephosphorylation, increased cytosolic Ca2+ release, and platelet activation with fibrinogen binding to integrin αIIbβ3, promoting aggregation and thrombus formation. When LRP5 is inhibited, P2Y12 signaling is attenuated, leading to higher cAMP levels, increased VASP phosphorylation, and suppression of Ca2+ mobilization. Consequently, platelet activation and aggregation are reduced, thereby decreasing thrombus formation without significantly increasing bleeding risk.
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Gawaz et al. (2025) conducted a review in Thrombosis. LRP5 inhibition was evaluated on Thrombus formation and bleeding risk. LRP5 inhibition attenuates P2Y12 signaling, reducing platelet activation and thrombus formation without significantly increasing bleeding risk.
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