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

Abstract

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.

• Authors: 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
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 194 Pg. 114822 (12 2021) ISSN: 1873-2968 [Electronic] England
• PMID: 34748820 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• NOD2 protein, human
• Nod2 Signaling Adaptor Protein
• P2RY12 protein, human
• Platelet Aggregation Inhibitors
• Receptors, Purinergic P2Y12
• Prasugrel Hydrochloride

Topics

• Animals
• Cell Line
• Female
• Humans
• Male
• Megakaryocytes (drug effects, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Middle Aged
• Nod2 Signaling Adaptor Protein (biosynthesis)
• Platelet Activation (drug effects, physiology)
• Platelet Aggregation Inhibitors (pharmacology, therapeutic use)
• Prasugrel Hydrochloride (pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Receptors, Purinergic P2Y12 (biosynthesis)
• Sepsis (metabolism)
• Thrombosis (metabolism)
• Up-Regulation (drug effects, physiology)