FUNDC2 regulates platelet activation through AKT/GSK-3β/cGMP axis. Issue 11 (21st December 2018)

• Record Type: Journal Article
• Authors: Ma, Qi; Zhang, Weilin; Zhu, Chongzhuo; Liu, Junling; Chen, Quan
• Is Part Of: Cardiovascular research. Volume 115:Issue 11(2019)
• Page Start: 1672
• Page End: 1679
• Publication Date: 2018-12-21
• Subjects: FUNDC2 -- Platelet activation -- AKT; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvy311
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: Aims: AKT kinase is vital for regulating signal transduction in platelet aggregation. We previously found that mitochondrial protein FUNDC2 mediates phosphoinositide 3-kinase (PI3K)/phosphatidylinositol-3, 4, 5-trisphosphate (PIP3)-dependent AKT phosphorylation and regulates platelet apoptosis. The aim of this study was to evaluate the role of FUNDC2 in platelet activation and aggregation. Methods and results: We demonstrated that FUNDC2 deficiency diminished platelet aggregation in response to a variety of agonists, including adenosine 5′-diphosphate (ADP), collagen, ristocetin/VWF, and thrombin. Consistently, in vivo assays of tail bleeding and thrombus formation showed that FUNDC2-knockout mice displayed deficiency in haemostasis and thrombosis. Mechanistically, FUNDC2 deficiency impairs the phosphorylation of AKT and downstream GSK-3β in a PI3K-dependent manner. Moreover, cGMP also plays an important role in FUNDC2/AKT-mediated platelet activation. This FUNDC2/AKT/GSK-3β/cGMP axis also regulates clot retraction of platelet-rich plasma. Conclusion: FUNDC2 positively regulates platelet functions via AKT/GSK-3β/cGMP signalling pathways, which provides new insight for platelet-related diseases. Graphical Abstract: