Abstract | BACKGROUND: METHOD AND RESULTS: Using reverse transcription polymerase chain reaction and Western blot, we show that both human and mouse platelets express NOD2, and its agonist muramyl dipeptide induced NOD2 activation as evidenced by receptor dimerization. NOD2 activation potentiates platelet aggregation and secretion induced by low concentrations of thrombin or collagen, and clot retraction, as well. These potentiating effects of muramyl dipeptide were not seen in platelets from NOD2-deficient mice. Plasma from septic patients also potentiates platelet aggregation induced by thrombin or collagen NOD2 dependently. Using intravital microscopy, we found that muramyl dipeptide administration accelerated in vivo thrombosis in a FeCl3-injured mesenteric arteriole thrombosis mouse model. Platelet depletion and transfusion experiments confirmed that NOD2 from platelets contributes to the in vivo thrombosis in mice. NOD2 activation also accelerates platelet-dependent hemostasis. We further found that platelets express receptor-interacting protein 2, and provided evidence suggesting that mitogen activated-protein kinase and nitric oxide/ soluble guanylyl cyclase/cGMP/ protein kinase G pathways downstream of receptor-interacting protein mediate the role of NOD2 in platelets. Finally, muramyl dipeptide stimulates proinflammatory cytokine interleukin-1β maturation and accumulation in human and mouse platelets NOD2 dependently. CONCLUSIONS:
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Authors | Si Zhang, Shenghui Zhang, Liang Hu, Lili Zhai, Ruyi Xue, Jianqin Ye, Leilei Chen, Guanjun Cheng, Jozef Mruk, Satya P Kunapuli, Zhongren Ding |
Journal | Circulation
(Circulation)
Vol. 131
Issue 13
Pg. 1160-70
(Mar 31 2015)
ISSN: 1524-4539 [Electronic] United States |
PMID | 25825396
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | © 2015 American Heart Association, Inc. |
Chemical References |
- IL1B protein, mouse
- Interleukin-1beta
- NOD2 protein, human
- Nod2 Signaling Adaptor Protein
- Nod2 protein, mouse
- Nitric Oxide
- Acetylmuramyl-Alanyl-Isoglutamine
- RIPK2 protein, human
- Receptor-Interacting Protein Serine-Threonine Kinase 2
- Receptor-Interacting Protein Serine-Threonine Kinases
- Ripk2 protein, mouse
- Cyclic GMP
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Topics |
- Acetylmuramyl-Alanyl-Isoglutamine
(pharmacology)
- Animals
- Bacteremia
(blood)
- Blood Platelets
(drug effects, metabolism)
- Clot Retraction
(physiology)
- Cyclic GMP
(blood)
- Dimerization
- Hemostasis
(physiology)
- Humans
- Inflammation
(blood)
- Interleukin-1beta
(blood)
- MAP Kinase Signaling System
(physiology)
- Mice
- Mice, Inbred NOD
- Nitric Oxide
(blood)
- Nod2 Signaling Adaptor Protein
(agonists, biosynthesis, blood, physiology)
- Platelet Activation
(drug effects, physiology)
- Receptor-Interacting Protein Serine-Threonine Kinase 2
(biosynthesis)
- Receptor-Interacting Protein Serine-Threonine Kinases
(biosynthesis)
- Signal Transduction
(physiology)
- Thrombosis
(blood)
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