Thrombomodulin, alarmin signaling, and copeptin: cross-talk between obesity and acute ischemic stroke initiation and severity in Egyptians
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Acute ischemic stroke (AIS) is followed by a strong inflammatory response contributing to brain damage and making early diagnosis and treatment inevitable. Hence, obesity is a state of chronic inflammation with amplified oxidative stress; this study aimed to assess the role played by thrombomodulin (TM)/alarmin signaling pathway and copeptin in AIS initiation and severity in addition to the implication of abnormal body weight. The study was conducted on 50 participants; 30 were patients with AIS (15 overweight/obese and 15 normal weight), 10 were overweight/obese, and 10 were normal weight. Plasma TM, copeptin, high mobility group box1 (HMGB1), and lipocalin 2 (LCN2) levels were immunoassayed. Toll-like receptor 4 (TLR4) mRNA expression was evaluated by real-time PCR, National Institutes of Health Stroke Scale (NIHSS), carotid intima media thickness; atherogenic index and glycemic status were also assessed. TM, copeptin, HMGB1, and LCN2 levels were significantly increased in overweight/obese AIS patients and in AIS patients with NIHSS score ≥ 7 when compared to other groups (p value=, ˂ 0.001*). Receiver operating characteristic (ROC) curve elaborated HMGB-1 and LCN2 as the best biomarker for diagnosis and prediction of AIS severity, respectively. Regression analysis avails LCN2 and TM as best biomarker for AIS severity predication. In conclusion, these results highlighted detrimental role of alarmin signaling with increased adaptive response to block this pathway through TM in addition to increased copeptin level as an acute damage marker and their tight relation to WC not to BMI in AIS which clarify the implication of central adiposity.
KeywordsAcute ischemic stroke (AIS) NIHSS score Carotid intima media thickness (CIMT) Thrombomodulin High mobility group box-1 (HMGB1) Lipocalin 2 (LCN) Toll-like receptor-4 (TLR4)
We would like to thank Dr. Zaytoun H. (Radiology Department, Tanta University) for the radiological examinations.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
The Ethical Committee of Tanta Faculty of Medicine approved this study (31649).
- 1.Bonaventura A, Liberale L, Vecchié A et al (2016) Update on inflammatory biomarkers and treatments in ischemic stroke. Int J Mol Sci 17(12). https://doi.org/10.3390/ijms17121967
- 5.Gunasekaran MK, Virama-Latchoumy AL, Girard AC, Planesse C, Guérin-Dubourg A, Ottosson L, Andersson U, Césari M, Roche R, Hoareau L (2016) TLR4-dependant pro-inflammatory effects of HMGB1 on human adipocyte. Adipocyte 5:384–388. https://doi.org/10.1080/21623945.2016.1245818 CrossRefPubMedPubMedCentralGoogle Scholar
- 10.Wendt M, Ebinger M, Kunz A, Rozanski M, Waldschmidt C, Weber JE, Winter B, Koch PM, Nolte CH, Hertel S, Ziera T, Audebert HJ, STEMO Consortium (2015) Copeptin levels in patients with acute ischemic stroke and stroke mimics. Stroke 46:2426–2431. https://doi.org/10.1161/STROKEAHA.115.009877 CrossRefPubMedGoogle Scholar
- 14.Hacke W, Albers G, Al-Rawi Y et al (2005) The Desmoteplase in Acute Ischemic Stroke Trial (DIAS): a phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke 36(1):66–73. https://doi.org/10.1161/01.STR.0000149938.08731.2c CrossRefPubMedGoogle Scholar
- 15.Zineldeen DH, Keshk WA, Ghazy AH et al Sucrose non-fermenting AMPK related kinase/pentraxin 3 and DNA damage axis: a gate way to cardiovascular disease in systemic lupus erythematosus among Egyptian patients. Ann Clin Biochem 201653(Pt 2):240–251. https://doi.org/10.1177/0004563215578190
- 20.Katan M, Fluri F, Morgenthaler NG, Schuetz P, Zweifel C, Bingisser R, MÃ¼ller K, Meckel S, Gass A, Kappos L, Steck AJ, Engelter ST, MÃ¼ller B, Christ-Crain M (2009) Copeptin: a novel, independent prognostic marker in patients with ischemic stroke. Ann Neurol 66:799–808. https://doi.org/10.1002/ana.21783 CrossRefPubMedGoogle Scholar
- 23.Zeljkovic A, Vekic J, Spasojevic-Kalimanovska V, Jelic-Ivanovic Z, Bogavac-Stanojevic N, Gulan B, Spasic S (2010) LDL and HDL subclasses in acute ischemic stroke: prediction of risk and short-term mortality. Atherosclerosis 210(2):548–554. https://doi.org/10.1016/j.atherosclerosis.2009.11.040 CrossRefPubMedGoogle Scholar
- 25.Haq S, Mathur M, Singh J et al (2017) Colour Doppler evaluation of extracranial carotid artery in patients presenting with acute ischemic stroke and correlation with various risk factors. J Clin Diagn Res 11(3):TC01–TC05. https://doi.org/10.7860/JCDR/2017/25493.9541 PubMedPubMedCentralGoogle Scholar
- 26.Faraco G, Fossati S, Bianchi ME, Patrone M, Pedrazzi M, Sparatore B, Moroni F, Chiarugi A (2007) High mobility group box 1 protein is released by neural cells upon different stresses and worsens ischemic neurodegeneration in vitro and in vivo. J Neurochem 103:590–603. https://doi.org/10.1111/j.1471-4159.2007.04788.x CrossRefPubMedGoogle Scholar
- 27.Wu D, Sheu JS, Liu HC, Yuan RY, Yu JM, Sheu JJ, Hung CH, Hu CJ (2012) Increase of toll-like receptor 4 but decrease of interleukin-8 mRNA expression among ischemic stroke patients under aspirin treatment. Clin Biochem 45:1316–1319. https://doi.org/10.1016/j.clinbiochem.2012.04.022 CrossRefPubMedGoogle Scholar
- 29.Kalinina N, Agrotis A, Antropova Y et al (2004) Increased expression of the DNA-binding cytokine HMGB1 in human atherosclerotic lesions: role of activated macrophages and cytokines. Arterioscler Thromb Vasc Biol 24:2320–2325. https://doi.org/10.1161/01.ATV.0000145573.36113.8a CrossRefPubMedGoogle Scholar
- 32.Nam Y, Kim JH, Seo M, Kim JH, Jin M, Jeon S, Seo JW, Lee WH, Bing SJ, Jee Y, Lee WK, Park DH, Kook H, Suk K (2014) Lipocalin-2 protein deficiency ameliorates experimental autoimmune encephalomyelitis: the pathogenic role of lipocalin-2 in the central nervous system and peripheral lymphoid tissues. J Biol Chem 289:16773–16789. https://doi.org/10.1074/jbc.M113.542282 CrossRefPubMedPubMedCentralGoogle Scholar
- 34.Jin M, Kim JH, Jang E, Lee YM, Han HS, Woo DK, Park DH, Kook H, Suk K (2014) Lipocalin-2 deficiency attenuates neuroinflammation and brain injury after transient middle cerebral artery occlusion in mice. J Cereb Blood Flow Metab 34:1306–1314. https://doi.org/10.1038/jcbfm.2014.83 CrossRefPubMedPubMedCentralGoogle Scholar
- 35.Song E, Jahng JW, Chong LP, Sung HK, Han M, Luo C, Wu D, Boo S, Hinz B, Cooper MA, Robertson AA, Berger T, Mak TW, George I, Schulze PC, Wang Y, Xu A, Sweeney G (2017) Lipocalin-2 induces NLRP3 inflammasome activation via HMGB1 induced TLR4 signaling in heart tissue of mice under pressure overload challenge. Am J Transl Res 9:2723–2735PubMedPubMedCentralGoogle Scholar
- 38.Meyer AA, Kundt G, Steiner M, Schuff-Werner P, Kienast W (2006) Impaired flow-mediated vasodilation, carotid artery intima-media thickening, and elevated endothelial plasma markers in obese children: the impact of cardiovascular risk factors. Pediatrics 117:1560–1567. https://doi.org/10.1542/peds.2005-2140 CrossRefPubMedGoogle Scholar
- 40.Jochberger S, Mayr VD, Luckner G, Wenzel V, Ulmer H, Schmid S, Knotzer H, Pajk W, Hasibeder W, Friesenecker B, Mayr AJ, Dünser MW (2006) Serum vasopressin concentrations in critically ill patients. Crit Care Med 34:293–299. https://doi.org/10.1097/01.ccm.0000198528.56397.4f CrossRefPubMedGoogle Scholar