LRP5 Protein Identified as Novel Target for Safer Antithrombotic Therapies With Reduced Bleeding Risk
核心洞察
Researchers from IR Sant Pau (搜索) and CIBERCV (搜索) have identified LRP5 (搜索) as a new protein directly involved in platelet aggregation and arterial thrombus formation, published in the European Heart Journal.
Genetic deletion and pharmacological inhibition of LRP5 (搜索) significantly reduced platelet activation and thrombus formation in preclinical models with markedly lower bleeding impact than aspirin or clopidogrel.
The study reveals a direct interaction between LRP5 (搜索) and the P2Y12 (搜索) receptor, identifying LRP5 as a key regulator of platelet response rather than a classical coagulation blocker.
A study published in the European Heart Journal has identified the LRP5 (搜索) protein as a previously unrecognized player in platelet activation and arterial thrombus formation, offering a potential new avenue for developing antithrombotic therapies with significantly lower bleeding risk — one of the most persistent challenges in cardiovascular medicine.
Researchers from the Sant Pau Research Institute (IR Sant Pau (搜索)) and the Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV (搜索)) demonstrated for the first time that LRP5 (搜索), a protein known primarily for its role in the WNT signaling pathway, is directly involved in platelet aggregation. The significance of the discovery prompted the European Heart Journal to simultaneously publish an independent editorial focused on new antithrombotic strategies capable of reducing bleeding risk.
"We have observed that both the genetic deletion of LRP5 (搜索) and its pharmacological inhibition very significantly reduce platelet activation and thrombus formation in preclinical models, but with a much lower bleeding impact than that of classic antiplatelet agents such as aspirin or clopidogrel," said Dr. Maria Borrell-Pages, researcher in the Molecular Pathology and Therapeutics of Atherothrombotic and Ischemic Diseases group at IR Sant Pau (搜索) and CIBERCV (搜索), and corresponding author of the study.
A New Pathway in Thrombus Formation
The research team combined murine models deficient in LRP5 (搜索) with experiments using human blood and platelets to dissect the protein's role. Their analyses revealed that the absence of LRP5 significantly reduces platelets' ability to adhere to collagen and aggregate following stimulation with ADP and collagen — two central mechanisms driving thrombus formation.
In experimental models of arterial thrombosis (搜索), the results were striking. Normal animals developed complete occlusion of the carotid artery in approximately 21 minutes, whereas LRP5 (搜索)-deficient mice did not fully block the vessel during the entire 30-minute experiment. The researchers also observed lower deposition of platelets and fibrinogen on the vascular wall, further reinforcing the antithrombotic effect associated with LRP5 inhibition.
"What we see is that LRP5 (搜索) participates in central mechanisms of platelet activation and communication," explained Dr. Borrell-Pages. "Inhibiting this protein alters key processes needed to stabilize and amplify thrombus formation."
Pharmacological inhibition of LRP5 (搜索) in human blood produced consistent results, reducing both platelet aggregation and thrombus formation under high-flow conditions and reproducing the behavior observed in animal models. Critically, the impact on bleeding was clearly lower than that observed with classic antiplatelet agents. In animal models, bleeding time was much lower than that recorded after treatment with acetylsalicylic acid or clopidogrel.
Direct Interaction With the P2Y12 Receptor
One of the study's most important mechanistic findings is the identification of a direct interaction between LRP5 (搜索) and the platelet P2Y12 (搜索) receptor — the very target of widely prescribed antiplatelet drugs including clopidogrel, prasugrel, and ticagrelor. The IR Sant Pau (搜索) and CIBERCV (搜索) teams showed that LRP5 helps regulate P2Y12 function during platelet activation. When LRP5 is blocked or absent, P2Y12 loses part of its ability to transmit the signals that activate and aggregate platelets.
LRP5 (搜索)-deficient platelets also exhibited alterations in the release of molecules stored in their granules, a process essential for amplifying thrombus formation. The researchers detected lower release of serotonin and proteins associated with platelet activation, as well as changes in the phosphorylation of VASP, a functional marker closely tied to P2Y12 (搜索) activity.
"This tells us that LRP5 (搜索) acts as a key regulator of the platelet response," said Dr. Borrell-Pages. "We are not directly blocking the classic coagulation mechanisms, but rather modulating processes that help amplify and stabilize thrombus formation." She added that the finding opens a new line of investigation: "The possibility of acting on regulatory proteins involved in platelet activation, and not only on classic receptors, could help develop more selective therapies in the future that are potentially safer."
Toward Safer Antithrombotic Therapies
The authors emphasize that the work remains at a preclinical stage and that further research is required before these findings can reach clinical practice. LRP5 (搜索) participates in multiple physiological functions, including cardiovascular, neuronal, and bone metabolism processes, meaning future therapeutic development will need to pursue selective strategies specifically targeting platelets.
Nonetheless, the study positions LRP5 (搜索) as a new potential therapeutic target in thrombosis (搜索) and offers a fresh approach to addressing one of the major limitations of current antiplatelet treatments: bleeding risk. In clinical practice, many patients with high cardiovascular risk require prolonged treatment to prevent new thrombotic events, yet the increased risk of bleeding can restrict use or limit therapeutic intensity.
The ability to slow thrombus formation without significantly altering physiological hemostasis represents one of the primary goals of contemporary cardiovascular research. "Our work opens up a new pathway to explore potentially more selective and safer antithrombotic treatments," concluded Dr. Borrell-Pages. "Although we are still at an experimental stage, identifying regulatory mechanisms of platelet activation such as LRP5 (搜索) can help us develop more precise therapies in the future."