Coenzyme Q10 Upregulates Platelet cAMP/PKA Pathway and Attenuates Integrin αIIbβ3 Signaling and Thrombus Growth

• Published in: Molecular nutrition & food research 2019-12, Vol.63 (23), p.e1900662-n/a
• Main Authors: Ya, Fuli, Xu, Xiaohong Ruby, Shi, Yilin, Gallant, Reid C., Song, Fenglin, Zuo, Xiao, Zhao, Yimin, Tian, Zezhong, Zhang, Cheng, Xu, Xiping, Ling, Wenhua, Ni, Heyu, Yang, Yan
• Format: Article
• Language: English
• Subjects: Agglomeration; Attenuation; Blood clots; Blood vessels; cAMP/PKA pathway; Cardiovascular diseases; Clinical trials; Coenzyme Q10; Cyclic AMP; dyslipidemic patients; Ferric chloride; Granular materials; Health risks; integrin αIIbβ3; Iron chlorides; Occlusion; Phosphodiesterase; Phosphorylation; Platelet aggregation; platelets; Protein kinase A; Secretion; Signal transduction; Signaling; Thromboembolism; Thrombosis
• ISSN: 1613-4125; 1613-4133
• DOI: 10.1002/mnfr.201900662

Scope Platelet integrin αIIbβ3 is the key mediator of atherothrombosis. Supplementation of coenzyme Q10 (CoQ10), a fat‐soluble molecule that exists in various foods, exerts protective cardiovascular effects. This study aims to investigate whether and how CoQ10 acts on αIIbβ3 signaling and thrombosis, the major cause of cardiovascular diseases. Methods and results Using a series of platelet functional assays in vitro, it is demonstrated that CoQ10 reduces human platelet aggregation, granule secretion, platelet spreading, and clot retraction. It is further demonstrated that CoQ10 inhibits platelet integrin αIIbβ3 outside‐in signaling. These inhibitory effects are mainly mediated by upregulating cAMP/PKA pathway, where CoQ10 stimulates the A2A adenosine receptor and decreases phosphodiesterase 3A phosphorylation. Moreover, CoQ10 attenuates murine thrombus growth and vessel occlusion in a ferric chloride (FeCl3)‐induced thrombosis model in vivo. Importantly, the randomized, double‐blind, placebo‐controlled clinical trial in dyslipidemic patients demonstrates that 24 weeks of CoQ10 supplementation increases platelet CoQ10 concentrations, enhances the cAMP/PKA pathway, and attenuates αIIbβ3 outside‐in signaling, leading to decreased platelet aggregation and granule release. Conclusion Through upregulating the platelet cAMP/PKA pathway, and attenuating αIIbβ3 signaling and thrombus growth, CoQ10 supplementation may play an important protective role in patients with risks of cardiovascular diseases. The extracellular coenzyme Q10 (CoQ10) stimulates platelet A2A adenosine receptor (A2AAR) and the intracellular CoQ10 inhibits phosphodiesterases 3A (PDE3A) activity, which contribute to the activation of the cAMP/PKA pathway. These effects result in attenuating platelet integrin αIIbβ3 outside‐in signaling and platelet function, and thus inhibiting thrombosis. Moreover, CoQ10‐enhanced cAMP/PKA pathway may also lead to the attenuation of αIIbβ3 inside‐out signaling.