RIP2 inhibits DOCK8-mediated platelet dense granule release and alleviates experimental myocardial infarction

  1. Jianjun Zhang
  2. Guanxing Pan
  3. Yangyang Liu
  4. Lin Chang
  5. Liang Hu
  6. Zhiyong Qi
  7. Zhiling Zhang
  8. Yan Zhang
  9. Si Zhang
  10. Jianlin Qiao
  11. Xiaodong Xi
  12. Kesheng Dai
  13. Jianzeng Dong
  14. Zhongren Ding
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Abstract

Objective

Receptor-interacting protein 2 (RIP2) is an essential mediator of inflammation and innate immunity downstream of pattern recognition receptors (PRRs). Platelets express RIP2, while its role in platelet activation, thrombosis, and myocardial infarction (MI) is unknown.

Approach and Results

Here we show that RIP2 deficiency enhances platelet dense granule secretion in response to GPIb and GPVI activation; platelet aggregation in whole blood and adhesion under arterial shear are also increased. Consistently, RIP2 inhibitor WEHI-345 potentiates human platelet dense granule secretion and inhibits RIP2 phosphorylation induced by thrombin and collagen. These phenotypes are translated into shorter bleeding time, accelerated FeCl 3 -induced arterial thrombosis. Importantly, platelets from patients with coronary artery disease and mice with atherosclerosis express lower RIP2, and RIP2 deficiency deteriorates MI and cardiac function in a mouse ischemia/reperfusion model. Mechanistically, we found that platelets express dedicator of cytogenesis protein 8 (DOCK8), which is sequestered by phosphorylated RIP2 (p-RIP2), causing inhibition of Cdc42 activation and subsequent dense granule release.

Conclusions

In conclusion, RIP2 inhibits platelet activation, thrombosis, and ameliorates MI. Our results also suggest that a novel PRR-independent pathway, p-RIP2-DOCK8-Cdc42, negatively regulates platelet activation downstream of GPIb and GPVI. Platelet RIP2 pathway may be promising for therapeutic intervention of atherothrombotic diseases from early atherosclerosis stage to arterial thrombosis and MI.

Highlights

  • RIP2 inhibits platelet dense granule release NOD2-independenly via pRIP2-DOCK8-Cdc42.

  • The negative regulation of RIP2 on platelet activation is translated into enhanced thrombosis, exacerbated myocardial infarction (MI).

  • RIP2 pathway booster may be an approach for therapeutic intervention of atherothrombotic diseases.

Article activity feed

  1. Version published to 10.1101/2025.04.19.649674v1 on bioRxiv