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Elevated Serum Ninjurin-1 Is Associated with a High Risk of Large Artery Atherosclerotic Acute Ischemic Stroke

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Abstract

Ninjurin-1 is a novel adhesion molecule which is involved in many inflammatory diseases. Functional blockage of Ninjurin-1 has exerted an atheroprotective effect. The aim of the study is to explore the association between serum Ninjurin-1 and the risk of large artery atherosclerotic acute ischemic stroke. From August 2020 through December 2021, patients with large artery atherosclerotic acute ischemic stroke (LAA-AIS) admitted to the First Hospital Affiliated to Soochow University, and age- and sex-matched controls free of ischemic stroke were recruited. Serum Ninj1 was measured with an enzyme-linked immunosorbent assay. Multivariable logistic regression models were used to calculate the odds ratios and 95% confidence intervals of LAA-AIS associated with serum Ninj1 levels, and receiver operating characteristic (ROC) curves were performed to assess the improvement value of Ninj1 for the prediction of LAA-AIS after adding Ninj1 to established risk factors. Of the 110 patients and 110 age- and sex-matched controls free of ischemic stroke enrolled, serum Ninj1 levels in LAA-AIS patients were significantly higher than that in control group (142.70 ng/ml [IQR: 110.41–163.44] vs 101.62 ng/ml [IQR: 86.63–120.86], p < 0.001). In multivariable analysis, Ninj1 levels were expressed as continuous variable and ordinal variable (tertiles), and it turned out that Ninj1 levels were positively associated with increased risk of LAA-AIS, especially in tertile3 compared with tertile1 (adjusted OR = 12.567, 95%CI: 5.148–30.678, p < 0.001), and the adjusted odds OR per 10 ng/ml increment was 1.541, 95%CI: 1.348–1.763, p < 0.001. Furthermore, adding Ninj1 to a multivariate logistic model including conventional risk factors associated LAA-AIS improved the area under ROC curves from 0.787 to 0.874. Elevated circulating levels of Ninj1 were associated with increased risk of LAA-AIS, indicating that serum Ninj1 may act as a predictor independent of established conventional risk factors.

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Data Availability

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

AIS:

Acute ischemic stroke

LAA-AIS:

Large artery atherosclerotic acute ischemic stroke

ROC:

Receiver operating characteristic curve

ASCVD:

Atherosclerotic cardiovascular disease

CAD:

Coronary artery disease

TOAST criteria:

Trial of Org 10172 in Acute Stroke Treatment criteria

AUC:

Area under receiver operating characteristic curve

References

  1. Björkegren JLM, Lusis AJ. Atherosclerosis: Recent developments. Cell. 2022;185(10):1630–45. https://doi.org/10.1016/j.cell.2022.04.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Roth GA, Mensah GA, Johnson CO, Addolorato G, Ammirati E, Baddour LM, Barengo NC, Beaton AZ, Benjamin EJ, Benziger CP, Bonny A, Brauer M, Brodmann M, Cahill TJ, Carapetis J, Catapano AL, Chugh SS, Cooper LT, Coresh J, Criqui M, DeCleene N, Eagle KA, Emmons-Bell S, Feigin VL, Fernández-Solà J, Fowkes G, Gakidou E, Grundy SM, He FJ, Howard G, Hu F, Inker L, Karthikeyan G, Kassebaum N, Koroshetz W, Lavie C, Lloyd-Jones D, Lu HS, Mirijello A, Temesgen AM, Mokdad A, Moran AE, Muntner P, Narula J, Neal B, Ntsekhe M, Moraes de Oliveira G, Otto C, Owolabi M, Pratt M, Rajagopalan S, Reitsma M, Ribeiro ALP, Rigotti N, Rodgers A, Sable C, Shakil S, Sliwa-Hahnle K, Stark B, Sundström J, Timpel P, Tleyjeh IM, Valgimigli M, Vos T, Whelton PK, Yacoub M, Zuhlke L, Murray C, Fuster V, GBD-NHLBI-JACC Global Burden of Cardiovascular Diseases Writing Group. Global Burden of Cardiovascular Diseases and Risk Factors, 1990–2019: Update From the GBD 2019 Study. J Am Coll Cardiol. 2020;76(25):2982–3021. https://doi.org/10.1016/j.jacc.2020.11.010.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Fiolet ATL, Opstal TSJ, Mosterd A, Eikelboom JW, Jolly SS, Keech AC, Kelly P, Tong DC, Layland J, Nidorf SM, Thompson PL, Budgeon C, Tijssen JGP, Cornel JH. Efficacy and safety of low-dose colchicine in patients with coronary disease: a systematic review and meta-analysis of randomized trials. Eur Heart J. 2021;42(28):2765–75. https://doi.org/10.1093/eurheartj/ehab115.

    Article  CAS  PubMed  Google Scholar 

  4. Araki T, Milbrandt J. Ninjurin, a novel adhesion molecule, is induced by nerve injury and promotes axonal growth. Neuron. 1996;17(2):353–61. https://doi.org/10.1016/s0896-6273(00)80166-x.

    Article  CAS  PubMed  Google Scholar 

  5. Ahn BJ, Le H, Shin MW, Bae SJ, Lee EJ, Wee HJ, Cha JH, Lee HJ, Lee HS, Kim JH, Kim CY, Seo JH, Lo EH, Jeon S, Lee MN, Oh GT, Yin GN, Ryu JK, Suh JK, Kim KW. Ninjurin1 deficiency attenuates susceptibility of experimental autoimmune encephalomyelitis in mice. J Biol Chem. 2014;289(6):3328–38. https://doi.org/10.1074/jbc.M113.498212.

    Article  CAS  PubMed  Google Scholar 

  6. Ifergan I, Kebir H, Terouz S, Alvarez JI, Lécuyer MA, Gendron S, Bourbonnière L, Dunay IR, Bouthillier A, Moumdjian R, Fontana A, Haqqani A, Klopstein A, Prinz M, López-Vales R, Birchler T, Prat A. Role of Ninjurin-1 in the migration of myeloid cells to central nervous system inflammatory lesions. Ann Neurol. 2011;70(5):751–63. https://doi.org/10.1002/ana.22519.

    Article  CAS  PubMed  Google Scholar 

  7. Jennewein C, Sowa R, Faber AC, Dildey M, von Knethen A, Meybohm P, Scheller B, Dröse S, Zacharowski K. Contribution of Ninjurin1 to Toll-like receptor 4 signaling and systemic inflammation. Am J Respir Cell Mol Biol. 2015;53(5):656–63. https://doi.org/10.1165/rcmb.2014-0354OC.

    Article  CAS  PubMed  Google Scholar 

  8. Jang YS, Kang JH, Woo JK, Kim HM, Hwang JI, Lee SJ, Lee HY, Oh SH. Ninjurin1 suppresses metastatic property of lung cancer cells through inhibition of interleukin 6 signaling pathway. Int J Cancer. 2016;139(2):383–95. https://doi.org/10.1002/ijc.30021.

    Article  CAS  PubMed  Google Scholar 

  9. Choi S, Woo JK, Jang YS, Kang JH, Hwang JI, Seong JK, Yoon YS, Oh SH. Ninjurin1 plays a crucial role in pulmonary fibrosis by promoting interaction between macrophages and alveolar epithelial cells. Sci Rep. 2018;8(1):17542. https://doi.org/10.1038/s41598-018-35997-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kang JH, Woo JK, Jang YS, Oh SH. Radiation Potentiates Monocyte Infiltration into Tumors by Ninjurin1 Expression in Endothelial Cells. Cells. 2020;9(5):1086. https://doi.org/10.3390/cells9051086.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kayagaki N, Kornfeld OS, Lee BL, Stowe IB, O’Rourke K, Li Q, Sandoval W, Yan D, Kang J, Xu M, Zhang J, Lee WP, McKenzie BS, Ulas G, Payandeh J, Roose-Girma M, Modrusan Z, Reja R, Sagolla M, Webster JD, Cho V, Andrews TD, Morris LX, Miosge LA, Goodnow CC, Bertram EM, Dixit VM. NINJ1 mediates plasma membrane rupture during lytic cell death. Nature. 2021;591(7848):131–6. https://doi.org/10.1038/s41586-021-03218-7.

    Article  CAS  PubMed  Google Scholar 

  12. Wang Y, Shao F. NINJ1, rupturing swollen membranes for cataclysmic cell lysis. Mol Cell. 2021;81(7):1370–1. https://doi.org/10.1016/j.molcel.2021.03.005.

    Article  CAS  PubMed  Google Scholar 

  13. Jeon S, Kim TK, Jeong SJ, Jung IH, Kim N, Lee MN, Sonn SK, Seo S, Jin J, Kweon HY, Kim S, Shim D, Park YM, Lee SH, Kim KW, Cybulsky MI, Shim H, Roh TY, Park WY, Lee HO, Choi JH, Park SH, Oh GT. Anti-inflammatory actions of soluble Ninjurin-1 ameliorate atherosclerosis. Circulation. 2020;142(18):1736–51. https://doi.org/10.1161/CIRCULATIONAHA.120.046907.

    Article  CAS  PubMed  Google Scholar 

  14. Tan X, Zhang Y, Shao H. Healthy China 2030, a breakthrough for improving health. Glob Health Promot. 2019;26(4):96–9. https://doi.org/10.1177/1757975917743533.

    Article  PubMed  Google Scholar 

  15. Gimbrone MA Jr, García-Cardeña G. Endothelial cell dysfunction and the pathobiology of atherosclerosis. Circ Res. 2016;118(4):620–36. https://doi.org/10.1161/CIRCRESAHA.115.306301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ridker PM. From CANTOS to CIRT to COLCOT to Clinic: will all atherosclerosis patients soon be treated with combination lipid-lowering and inflammation-inhibiting agents? Circulation. 2020;141(10):787–9. https://doi.org/10.1161/CIRCULATIONAHA.119.045256.

    Article  PubMed  Google Scholar 

  17. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, Kastelein JJP, Cornel JH, Pais P, Pella D, Genest J, Cifkova R, Lorenzatti A, Forster T, Kobalava Z, Vida-Simiti L, Flather M, Shimokawa H, Ogawa H, Dellborg M, Rossi PRF, Troquay RPT, Libby P, Glynn RJ, CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377(12):1119–31. https://doi.org/10.1056/NEJMoa1707914.

    Article  CAS  PubMed  Google Scholar 

  18. Deftereos SG, Beerkens FJ, Shah B, Giannopoulos G, Vrachatis DA, Giotaki SG, Siasos G, Nicolas J, Arnott C, Patel S, Parsons M, Tardif JC, Kovacic JC, Dangas GD. Colchicine in cardiovascular disease: In-Depth Review. Circulation. 2022;145(1):61–78. https://doi.org/10.1161/CIRCULATIONAHA.121.056171.

    Article  CAS  PubMed  Google Scholar 

  19. Araki T, Zimonjic DB, Popescu NC, Milbrandt J. Mechanism of homophilic binding mediated by ninjurin, a novel widely expressed adhesion molecule. J Biol Chem. 1997;272(34):21373–80. https://doi.org/10.1074/jbc.272.34.21373.

    Article  CAS  PubMed  Google Scholar 

  20. Lee HJ, Ahn BJ, Shin MW, Jeong JW, Kim JH, Kim KW. Ninjurin1 mediates macrophage-induced programmed cell death during early ocular development. Cell Death Differ. 2009;16(10):1395–407. https://doi.org/10.1038/cdd.2009.78.

    Article  CAS  PubMed  Google Scholar 

  21. Choi H, Bae SJ, Choi G, Lee H, Son T, Kim JG, An S, Lee HS, Seo JH, Kwon HB, Jeon S, Oh GT, Surh YJ, Kim KW. Ninjurin1 deficiency aggravates colitis development by promoting M1 macrophage polarization and inducing microbial imbalance. FASEB J. 2020;34(6):8702–20. https://doi.org/10.1096/fj.201902753R.

    Article  CAS  PubMed  Google Scholar 

  22. Woo JK, Jang YS, Kang JH, Hwang JI, Seong JK, Lee SJ, Jeon S, Oh GT, Lee HY, Oh SH. Ninjurin1 inhibits colitis-mediated colon cancer development and growth by suppression of macrophage infiltration through repression of FAK signaling. Oncotarget. 2016;7(20):29592–604. https://doi.org/10.18632/oncotarget.9020.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Jeon S, Oh GT. Response by Jeon and Oh to Letter Regarding Article. Anti-inflammatory actions of soluble Ninjurin-1 ameliorate atherosclerosis. Circulation. 2021;143(19):e921–2. https://doi.org/10.1161/CIRCULATIONAHA.121.053671.

    Article  CAS  PubMed  Google Scholar 

  24. Lee HK, Kim ID, Lee H, Luo L, Kim SW, Lee JK. Neuroprotective and anti-inflammatory effects of a dodecamer peptide harboring Ninjurin 1 cell adhesion motif in the postischemic brain. Mol Neurobiol. 2018;55(7):6094–111. https://doi.org/10.1007/s12035-017-0810-1.

    Article  CAS  PubMed  Google Scholar 

  25. Wang X, Qin J, Zhang X, Peng Z, Ye K, Wu X, Yang X, Shi H, Zhao Z, Guo X, Liu X, Yin M, Lu X. Functional blocking of Ninjurin1 as a strategy for protecting endothelial cells in diabetes mellitus. Clin Sci (Lond). 2018;132(2):213–29. https://doi.org/10.1042/CS20171273.

    Article  CAS  PubMed  Google Scholar 

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Funding

This study was supported by National Natural Science Foundation of China (82071300), Suzhou Science and Technology Development Plan (SYSD2020073), The Stroke Team of Professor Fang Qi from the First Affiliated Hospital of Soochow University (SZYQTD202106); a follow-up study of cognitive impairment combined with depression in stroke patients (SYSD2020073); Suzhou Industrial Park Jinji Lake Health Talents (202110).

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Author notes

  1. Nan Dong and Xuan Wu contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, the First Affiliated Hospital of Soochow University, Suzhou, 215000, China

    Nan Dong, Hui Wang, Liqiang Yu, Hongru Zhao & Qi Fang

  2. Department of Neurology, Suzhou Industrial Park Xinghai Hospital, Suzhou, 215000, China

    Nan Dong & Xianghong Guo

  3. Department of Neurology, Affiliated Hospital of Yangzhou University, Yangzhou, 225009, China

    Xuan Wu

  4. Department of Neurology, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou, 215000, China

    Ting Hong

  5. Department of Neurology, Lianyungang Second People’s Hospital, Lianyungang, 222000, China

    Xiaozhu Shen

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  1. Nan Dong
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Contributions

QF conceived and designed the research. ND analyzed the data and drafted the manuscript. ND, XW, TH, XS, XG, HW, LY, and HZ collected the data and performed the research. All authors reviewed and edited the manuscript and approved the final version of the manuscript.

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Correspondence to Hongru Zhao or Qi Fang.

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The authors declare no competing interests.

Ethics Approval

The protocol of the study conforms to the ethical guidelines mentioned in the Declaration of Helsinki and was approved by the Ethics Committee of the First Hospital Affiliated to Soochow University (No. 2021–07-01). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

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Dong, N., Wu, X., Hong, T. et al. Elevated Serum Ninjurin-1 Is Associated with a High Risk of Large Artery Atherosclerotic Acute Ischemic Stroke. Transl. Stroke Res. 14, 465–471 (2023). https://doi.org/10.1007/s12975-022-01077-6

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