LAUSR

AIMS Galectin-3, a β-galactoside-binding lectin, is abnormally increased in cardiovascular disease. Plasma Galectin-3 receives a Class II recommendation for heart failure management and has been extensively studied for multiple cellular functions. The direct effects of Galectin-3 on platelet activation remain unclear. This study explores the direct effects of Galectin-3 on platelet activation and thrombosis. METHODS AND RESULTS A strong positive correlation between plasma Galectin-3 concentration and platelet aggregation or whole blood thrombus formation was observed in patients with coronary artery disease (CAD). Multiple platelet function studies demonstrated that Galectin-3 directly potentiated platelet activation and in vivo thrombosis. Mechanistic studies using the Dectin-1 inhibitor, laminarin, and Dectin-1-/- mice revealed that Galectin-3 bound to and activated Dectin-1, a receptor not previously reported in platelets, to phosphorylate spleen tyrosine kinase and thus increased Ca2+ influx, protein kinase C activation, and reactive oxygen species production to regulate platelet hyperreactivity. TD139, a Galectin-3 inhibitor in a Phase II clinical trial, concentration dependently suppressed Galectin-3-potentiated platelet activation and inhibited occlusive thrombosis without exacerbating haemorrhage in ApoE-/- mice, which spontaneously developed increased plasma Galectin-3 levels. TD139 also suppressed microvascular thrombosis to protect the heart from myocardial ischaemia-reperfusion injury in ApoE-/- mice. CONCLUSION Galectin-3 is a novel positive regulator of platelet hyperreactivity and thrombus formation in CAD. As TD139 has potent antithrombotic effects without bleeding risk, Galectin-3 inhibitors may have therapeutic advantages as potential antiplatelet drugs for patients with high plasma Galectin-3 levels. KEY QUESTION Impact of Galectin-3 on platelet activation and arterial thrombus formation. KEY FINDING Galectin-3 directly potentiates platelet activation and thrombus formation via Dectin-1 activation. TD139, a Galectin-3 inhibitor, protects the heart from myocardial ischaemia-reperfusion injury by suppressing Galectin-3-potentiated platelet activation and thrombosis without exacerbating haemorrhage in ApoE-/- mice. TAKE-HOME MESSAGE Galectin-3 enhances platelet aggregation and thrombosis in patients with coronary artery disease; and Galectin-3 inhibitors may be considered for patients with high plasma Galectin-3 levels to prevent platelet hyperreactivity and thrombotic events.