NOD2-mediated P2Y12 upregulation increases platelet activation and thrombosis in sepsis

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作者：Haoxuan Zhong, Maieryemu Waresi, Wei Zhang, Liping Han, Yikai Zhao, Yufei Chen, Peng Zhou, Lin Chang, Guanxing Pan, Bangwei Wu, Jian Li, Si Zhang, Haiming Shi, Xinping Luo, Wen Gao, Zhiyong Qi, Zhongren Ding
期刊：BIOCHEMICAL PHARMACOLOGY
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Background:Platelets from septic patients exhibit increased reactivity. However, the underlying mechanism of sepsis-induced platelet hyperactivity is still not completely understood.

Objective:P2Y₁₂ is a central receptor for platelet activation. In this study, we investigated the role of platelet P2Y₁₂ in platelet hyperactivity during sepsis.

Methods:We measured platelet P2Y₁₂ expression and aggregation in response to ADP in septic patients and cecal ligation and puncture (CLP)-treated mice. We also detected the downstream signaling of P2Y₁₂ in resting platelets from patients and mice with sepsis. The role of nucleotide-binding oligomerization domain 2 (NOD2)/RIP2/NF-κB/P65 pathway in sepsis-induced platelet P2Y₁₂ high expression was also investigated. Finally, we compared the antiplatelet and antithrombotic effects of clopidogrel, prasugrel, and ticagrelor in experimental sepsis in mice and rats.

Results:Compared to healthy subjects, platelets from septic patients exhibit P2Y₁₂ hyperactivity and higher P2Y₁₂ expression. pAkt is enhanced and pVASP is impaired in resting platelets from the patients, indicating the constitutive activation of platelet P2Y₁₂ receptor. Mouse sepsis model recapitulates the findings in septic patients. NOD2 deficiency attenuates sepsis-induced platelet P2Y₁₂ high expression, hyperactivity, and thrombosis. Prasugrel and ticagrelor are potent P2Y₁₂ inverse agonists, and exhibit superior antiplatelet and antithrombotic efficacy over clopidogrel in mice and rats with sepsis.

Conclusions:NOD2 activation upregulates platelet P2Y₁₂ expression, which is constitutively activated and contributes to platelet hyperactivity in septic status. Compared to clopidogrel, prasugrel and ticagrelor are potent P2Y₁₂ inverse agonists with superior antiplatelet and antithrombotic efficacy in experimental sepsis.