Evidence map›Paper›PMID 25825396›Full record

ArticleCirculation2015

Nucleotide-binding oligomerization domain 2 receptor is expressed in platelets and enhances platelet activation and thrombosis.

Si Zhang, Shenghui Zhang, Liang Hu, Lili Zhai, Ruyi Xue, Jianqin Ye, Leilei Chen, Guanjun Cheng, Jozef Mruk, Satya P Kunapuli and 1 more

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In one paragraph

Article in Circulation, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.

0numbers the graph read from it
0cells of the map it votes in
42citing papers in PubMed
3.3field-weighted citation impact, top 7% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

42 citing papers in PubMed, 94 citations in OpenAlex.

  1. Review
  2. Review
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  4. Beyond hemostasis, the immunomodulatory nature of platelets.Research and practice in thrombosis and haemostasis · 2025
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  11. Article
  12. Platelet P2YBritish journal of pharmacology · 2024
    Review
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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

11 authors at 5 institutions in 2 countries.

Si ZhangFrom Key Laboratory of Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China (Si Zhang, Shenghui Zhang, L.H., L.Z., J.Y., L.C., Z.D.); Department of Internal Medicine, and Institute of Liver Disease, Fudan University Zhongshan Hospital, Shanghai, China (R.X.); Thoracic Oncology Research Laboratory, University of Pennsylvania, Philadelphia, (G.C.); Department of Internal Medicine, University of Kansas School of Medicine, Wichita (J.S.M.); and Department of Physiology and Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA (S.P.K.).
Shenghui ZhangFrom Key Laboratory of Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China (Si Zhang, Shenghui Zhang, L.H., L.Z., J.Y., L.C., Z.D.); Department of Internal Medicine, and Institute of Liver Disease, Fudan University Zhongshan Hospital, Shanghai, China (R.X.); Thoracic Oncology Research Laboratory, University of Pennsylvania, Philadelphia, (G.C.); Department of Internal Medicine, University of Kansas School of Medicine, Wichita (J.S.M.); and Department of Physiology and Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA (S.P.K.).
Liang HuFrom Key Laboratory of Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China (Si Zhang, Shenghui Zhang, L.H., L.Z., J.Y., L.C., Z.D.); Department of Internal Medicine, and Institute of Liver Disease, Fudan University Zhongshan Hospital, Shanghai, China (R.X.); Thoracic Oncology Research Laboratory, University of Pennsylvania, Philadelphia, (G.C.); Department of Internal Medicine, University of Kansas School of Medicine, Wichita (J.S.M.); and Department of Physiology and Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA (S.P.K.).
Lili ZhaiFrom Key Laboratory of Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China (Si Zhang, Shenghui Zhang, L.H., L.Z., J.Y., L.C., Z.D.); Department of Internal Medicine, and Institute of Liver Disease, Fudan University Zhongshan Hospital, Shanghai, China (R.X.); Thoracic Oncology Research Laboratory, University of Pennsylvania, Philadelphia, (G.C.); Department of Internal Medicine, University of Kansas School of Medicine, Wichita (J.S.M.); and Department of Physiology and Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA (S.P.K.).
Ruyi XueFrom Key Laboratory of Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China (Si Zhang, Shenghui Zhang, L.H., L.Z., J.Y., L.C., Z.D.); Department of Internal Medicine, and Institute of Liver Disease, Fudan University Zhongshan Hospital, Shanghai, China (R.X.); Thoracic Oncology Research Laboratory, University of Pennsylvania, Philadelphia, (G.C.); Department of Internal Medicine, University of Kansas School of Medicine, Wichita (J.S.M.); and Department of Physiology and Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA (S.P.K.).
Jianqin YeFrom Key Laboratory of Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China (Si Zhang, Shenghui Zhang, L.H., L.Z., J.Y., L.C., Z.D.); Department of Internal Medicine, and Institute of Liver Disease, Fudan University Zhongshan Hospital, Shanghai, China (R.X.); Thoracic Oncology Research Laboratory, University of Pennsylvania, Philadelphia, (G.C.); Department of Internal Medicine, University of Kansas School of Medicine, Wichita (J.S.M.); and Department of Physiology and Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA (S.P.K.).
Leilei ChenFrom Key Laboratory of Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China (Si Zhang, Shenghui Zhang, L.H., L.Z., J.Y., L.C., Z.D.); Department of Internal Medicine, and Institute of Liver Disease, Fudan University Zhongshan Hospital, Shanghai, China (R.X.); Thoracic Oncology Research Laboratory, University of Pennsylvania, Philadelphia, (G.C.); Department of Internal Medicine, University of Kansas School of Medicine, Wichita (J.S.M.); and Department of Physiology and Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA (S.P.K.).
Guanjun ChengFrom Key Laboratory of Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China (Si Zhang, Shenghui Zhang, L.H., L.Z., J.Y., L.C., Z.D.); Department of Internal Medicine, and Institute of Liver Disease, Fudan University Zhongshan Hospital, Shanghai, China (R.X.); Thoracic Oncology Research Laboratory, University of Pennsylvania, Philadelphia, (G.C.); Department of Internal Medicine, University of Kansas School of Medicine, Wichita (J.S.M.); and Department of Physiology and Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA (S.P.K.).
Jozef MrukFrom Key Laboratory of Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China (Si Zhang, Shenghui Zhang, L.H., L.Z., J.Y., L.C., Z.D.); Department of Internal Medicine, and Institute of Liver Disease, Fudan University Zhongshan Hospital, Shanghai, China (R.X.); Thoracic Oncology Research Laboratory, University of Pennsylvania, Philadelphia, (G.C.); Department of Internal Medicine, University of Kansas School of Medicine, Wichita (J.S.M.); and Department of Physiology and Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA (S.P.K.).
Satya P KunapuliFrom Key Laboratory of Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China (Si Zhang, Shenghui Zhang, L.H., L.Z., J.Y., L.C., Z.D.); Department of Internal Medicine, and Institute of Liver Disease, Fudan University Zhongshan Hospital, Shanghai, China (R.X.); Thoracic Oncology Research Laboratory, University of Pennsylvania, Philadelphia, (G.C.); Department of Internal Medicine, University of Kansas School of Medicine, Wichita (J.S.M.); and Department of Physiology and Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA (S.P.K.).
Zhongren DingFrom Key Laboratory of Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China (Si Zhang, Shenghui Zhang, L.H., L.Z., J.Y., L.C., Z.D.); Department of Internal Medicine, and Institute of Liver Disease, Fudan University Zhongshan Hospital, Shanghai, China (R.X.); Thoracic Oncology Research Laboratory, University of Pennsylvania, Philadelphia, (G.C.); Department of Internal Medicine, University of Kansas School of Medicine, Wichita (J.S.M.); and Department of Physiology and Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA (S.P.K.). dingzr@fudan.edu.cn.
Fudan University · CNUniversity of Pennsylvania · USSun Yat-sen University · CNThe First Affiliated Hospital, Sun Yat-sen University · CNUniversity of Kansas · US

Funding

Functional PKC Isoforms in PlateletsR01HL093231 · NHLBI · TEMPLE UNIV OF THE COMMONWEALTH · PI KUNAPULI, SATYA P. · 2009 to 2017
$3.6M
Regulation and function of PDK1-Akt-Pyk2 axis in plateletsR01HL118593 · NHLBI · TEMPLE UNIV OF THE COMMONWEALTH · PI KUNAPULI, SATYA P. · 2013 to 2016
$1.9M
NHLBI NIH HHS HL118593NHLBI NIH HHS HL93231NHLBI NIH HHS R01 HL093231NHLBI NIH HHS R01 HL118593
6 · The paper itself

Abstract

backgroundPattern recognition receptor nucleotide-binding oligomerization domain 2 (NOD2) is well investigated in immunity, but its expression and function in platelets has never been explored. METHOD AND

resultsUsing 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.

conclusionsNOD2 is expressed in platelets and functions in platelet activation and arterial thrombosis, possibly during infection. To our knowledge, this is the first study on NOD-like receptors in platelets that link thrombotic events to inflammation.

Indexed as

Acetylmuramyl-Alanyl-IsoglutamineAnimalsBacteremiaBlood PlateletsClot RetractionCyclic GMPDimerizationHemostasisHumansInflammationInterleukin-1betaMAP Kinase Signaling SystemMiceMice, Inbred NODNitric OxideNod2 Signaling Adaptor ProteinAcetylmuramyl-Alanyl-IsoglutamineCyclic GMPIL1B protein, mouseInterleukin-1betaNitric OxideNOD2 protein, humanNod2 protein, mouseNod2 Signaling Adaptor ProteinReceptor-Interacting Protein Serine-Threonine Kinase 2Receptor-Interacting Protein Serine-Threonine KinasesRIPK2 protein, humanRipk2 protein, mouseblood plateletsmitogen-activated protein kinasesnucleotide-binding oligomerization domain 2receptor-interacting protein serine-threonine kinase 2thrombosis

Identifiers

PMID25825396
PMCPMC4382913
OpenAlexW2001494483

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.