Galectin 3 enhances platelet aggregation and thrombosis via Dectin-1 activation: a translational study . (15th February 2022)

• Record Type: Journal Article
• Authors: Chen, Yufei; Fu, Wanrong; Zheng, Yunbo; Yang, Jing; Liu, Yangyang; Qi, Zhiyong; Wu, Meiling; Fan, Zhichao; Yin, Kanhua; Chen, Yunfeng; Gao, Wen; Ding, Zhongren; Dong, Jianzeng; Li, Qi; Zhang, Si; Hu, Liang
• Is Part Of: European heart journal. Volume 43:Number 37(2022)
• Page Start: 3556
• Page End: 3574
• Publication Date: 2022-02-15
• Subjects: Platelet hyperreactivity -- Cardiovascular diseases -- Galectin-3 -- Dectin-1 -- Antithrombotic -- TD139; Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; 616.12005
• DOI: 10.1093/eurheartj/ehac034
• Languages: English
• ISSNs: 0195-668X

Abstract

Abstract: 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 Ca 2+ 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. Structured Graphical Abstract: Structured Graphical Abstract Working model for plasma Galectin-3 directly potentiating platelet activation, and the platelet hyperreactivity suppressing effect of Galectin-3 inhibitor TD139 in coronary artery disease. Accumulated Galectin-3 in plasma directly activates Dectin-1 receptor to potentiate platelet activation (platelet aggregation and ATP release), which enhances in vivo thrombosis and myocardial ischaemia–reperfusion injury. Galectin-3 inhibitor TD139 specifically inhibits Galectin-3-induced platelet hyperreactivity to ameliorate atherothrombosis and myocardial infarction in coronary artery disease.