TY - JOUR
T1 - Galectin 3 enhances platelet aggregation and thrombosis via Dectin-1 activation
T2 - A translational study
AU - Chen, Yufei
AU - Fu, Wanrong
AU - Zheng, Yunbo
AU - Yang, Jing
AU - Liu, Yangyang
AU - Qi, Zhiyong
AU - Wu, Meiling
AU - Fan, Zhichao
AU - Yin, Kanhua
AU - Chen, Yunfeng
AU - Gao, Wen
AU - Ding, Zhongren
AU - Dong, Jianzeng
AU - Li, Qi
AU - Zhang, Si
AU - Hu, Liang
N1 - Publisher Copyright:
© 2022 The Author(s). Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved.
PY - 2022/10/7
Y1 - 2022/10/7
N2 - 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.
AB - 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.
KW - Antithrombotic
KW - Cardiovascular diseases
KW - Dectin-1
KW - Galectin-3
KW - Platelet hyperreactivity
KW - TD139
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U2 - 10.1093/eurheartj/ehac034
DO - 10.1093/eurheartj/ehac034
M3 - Article
C2 - 35165707
AN - SCOPUS:85132183475
SN - 0195-668X
VL - 43
SP - 3556
EP - 3574
JO - European Heart Journal
JF - European Heart Journal
IS - 37
ER -