Fuli Ya1,2,3, Xiaohong Ruby Xu4, Yilin Shi1,2,3, Reid C Gallant4, Fenglin Song5, Xiao Zuo2,3,6, Yimin Zhao2,3,6, Zezhong Tian2,3,6, Cheng Zhang7, Xiping Xu8, Wenhua Ling1,2,3, Heyu Ni4,9,10,11,12, Yan Yang2,3,6. 1. Department of Nutrition, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, 510080, China. 2. Guangdong Provincial Key Laboratory for Food, Nutrition and Health, Guangzhou, Guangdong Province, 510080, China. 3. Guangdong Province Engineering Laboratory for Nutrition Translation, Guangzhou, Guangdong Province, 510080, China. 4. Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, M5B 1W8, Canada. 5. School of Food Science, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, 510006, China. 6. School of Public Health (Shenzhen), Sun Yat-sen University, Guangzhou, Guangdong Province, 510006, China. 7. Department of Clinical Laboratory, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong Province, 510120, China. 8. National Clinical Research Center for Kidney Disease, Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, 510515, China. 9. Canadian Blood Services Centre for Innovation, Toronto, Ontario, M5G 2M1, Canada. 10. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, M5S 1A1, Canada. 11. Department of Medicine, University of Toronto, Toronto, Ontario, M5S 1A1, Canada. 12. Department of Physiology, University of Toronto, Toronto, Ontario, M5S 1A1, Canada.
Abstract
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.
RCT Entities:
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 humanplatelet 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 murinethrombus 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.
Authors: Gerwyn Morris; Basant K Puri; Lisa Olive; Andre Carvalho; Michael Berk; Ken Walder; Lise Tuset Gustad; Michael Maes Journal: BMC Med Date: 2020-10-19 Impact factor: 8.775