Abstract
Retinol-binding protein 4 (RBP4) is an adipocyte-secreted molecule and is associated with cardiovascular risk factors. The aim of this study was to assess the clinical significance of serum levels of RBP4 in Chinese patients with acute ischemic stroke (AIS). We sequentially screened patients with first-ever AIS who were admitted to our Hospital between September 2016 and October 2017. Serum levels of RBP4 were assayed with solid-phase sandwich ELISA, and severity of stroke was evaluated with the National Institutes of Health Stroke Scale (NIHSS) score on admission. We used logistic regression models to assess the relationship between RBP4 levels and stroke risk and severity. During the inclusion period, 323 patients completed the study. Our results indicated that the median serum RBP4 levels were significantly (P < 0.001) higher in patients with AIS than in those normal cases [28.9 (IQR, 17.3–39.6) μg/ml vs. 23.7 (14.6–32.3) μg/ml]. In logistic regression analysis, for each 1 unit increase of serum level of RBP4, the unadjusted and adjusted risks of AIS increased by 4% (OR 1.04 [95% CI 1.02–1.05], P < 0.001) and 3% (1.03 [1.01–1.04], P < 0.001), respectively. At admission, 116 patients (35.9%) had a minor stroke (NIHSS < 6). In logistic regression analysis, for each 1 unit increase of serum level of RBP4, the unadjusted and adjusted risks of moderate-to-high stroke increased by 7% (OR 1.07 [95% CI 1.05–1.09], P < 0.001) and 5% (1.05 [1.02–1.07], P < 0.001), respectively. Elevated levels of RBP4 could be considered an independent diagnosis marker of AIS. Elevated levels of RBP4 were significantly associated with higher stroke severity in Chinese sample.
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References
Adams HP, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE (1993) Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 24(1):35–41
Agasthi P, Aloor S, Chenna A, Harris R (2015) Association between serum retinol binding protein-4 level and coronary artery disease: a meta-analysis. Arterioscler Thromb Vasc Biol 35:A344
Alkharfy KM, Al-Daghri NM, Vanhoutte PM, Krishnaswamy S, Xu A (2012) Serum retinol-binding protein 4 as a marker for cardiovascular disease in women. PLoS One 7(10):e48612
Allen CL, Bayraktutan U (2009) Oxidative stress and its role in the pathogenesis of ischaemic stroke. Int J Stroke 4(6):461–470
Amarenco P, Cohen A, Tzourio C, Bertrand B, Hommel M, Besson G, Chauvel C, Touboul PJ, Bousser MG (1994) Atherosclerotic disease of the aortic arch and the risk of ischemic stroke. N Engl J Med 331(22):1474–1479
Bamford J, Sandercock P, Dennis M, Warlow C, Burn J (1991) Classification and natural history of clinically identifiable subtypes of cerebral infarction. Lancet 337(8756):1521–1526
Bobbert T, Raila J, Schwarz F, Mai K, Henze A, Pfeiffer AF et al (2010) Relation between retinol, retinol-binding protein 4, transthyretin and carotid intima media thickness. Atherosclerosis 213(2):549–551
Brott T, Adams HP, Olinger CP, Marler JR, Barsan WG, Biller J, Spilker J, Holleran R, Eberle R, Hertzberg V (1989) Measurements of acute cerebral infarction: a clinical examination scale. Stroke 20(7):864–870
Cabre A, Lazaro I, Girona J, Manzanares J, Marimon F, Plana N et al (2007) Retinol-binding protein 4 as a plasma biomarker of renal dysfunction and cardiovascular disease in type 2 diabetes. J Intern Med 262(4):496–503
Cabré A, Lázaro I, Girona J, Manzanares JM, Marimón F, Plana N et al (2008) Plasma fatty acid binding protein 4 is associated with atherogenic dyslipidemia in diabetes. J Lipid Res 49(8):1746–1751
Daubail B, Jacquin A, Guilland JC, Hervieu M, Osseby GV, Rouaud O, Giroud M, Béjot Y (2013) Serum 25-hydroxyvitamin D predicts severity and prognosis in stroke patients. Eur J Neurol 20(1):57–61
Ettehad D, Emdin CA, Kiran A, Anderson SG, Callender T, Emberson J et al (2016) Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet 387(10022):957–967
Farjo KM, Farjo RA, Halsey S, Moiseyev G, Ma JX (2012) Retinol-binding protein 4 induces inflammation in human endothelial cells by an NADPH oxidase-and nuclear factor kappa B-dependent and retinol-independent mechanism. Mol Cell Biol 32(24):5103–5115
Graham TE, Wason CJ, Blüher M, Kahn BB (2007) Shortcomings in methodology complicate measurements of serum retinol binding protein (RBP4) in insulin-resistant human subjects. Diabetologia 50(4):814–823
Ingelsson E, Sundström J, Melhus H, Michaëlsson K, Berne C, Vasan RS et al (2009) Circulating retinol-binding protein 4, cardiovascular risk factors and prevalent cardiovascular disease in elderly. Atherosclerosis 206(1):239–244
Ingelsson E, Lind L (2009) Circulating retinol-binding protein 4 and subclinical cardiovascular disease in the elderly. Diabetes Care 32(4):733–735
Kanoriya D, Pradeep AR, Mallika A, Singhal S, Garg V (2017) Correlation of crevicular fluid and serum levels of retinol-binding protein 4 and leptin in chronic periodontitis and obesity. Clin Oral Investig 21(7):2319–2325
Kouwenhoven M, Carlstrõm C, Õzenci V, Link H (2001) Matrix metalloproteinase and cytokine profiles in monocytes over the course of stroke. J Clin Immunol 21(5):365–375
Kraus BJ, Sartoretto JL, Polak P, Hosooka T, Shiroto T, Eskurza I et al (2015) Novel role for retinol-binding protein 4 in the regulation of blood pressure. FASEB J 29(8):3133–3140
Laakso M, Kuusisto J (2014) Insulin resistance and hyperglycaemia in cardiovascular disease development. Nat Rev Endocrinol 10(5):293–302
Lakhan SE, Kirchgessner A, Hofer M (2009) Inflammatory mechanisms in ischemic stroke: therapeutic approaches. J Transl Med 7(1):97
Lee SA, Kallianpur A, Xiang YB, Wen W, Cai Q, Liu D, Fazio S, Linton MF, Zheng W, Shu XO (2007) Intra-individual variation of plasma adipokine levels and utility of single measurement of these biomarkers in population-based studies. Cancer Epidemiol Prev Biomark 16(11):2464–2470
Liu G, Ding M, Chiuve SE, Rimm EB, Franks PW, Meigs JB, ... & Sun Q (2016) Plasma levels of fatty acid–binding protein 4, retinol-binding protein 4, high-molecular-weight adiponectin, and cardiovascular mortality among men with type 2 diabetes: a 22-year prospective study. Arteriosclerosis, thrombosis, and vascular biology 36:2259–2267
Liu Y, Wang D, Li D, Sun R, Xia M (2014) Associations of retinol-binding protein 4 with oxidative stress, inflammatory markers, and metabolic syndrome in a middle-aged and elderly Chinese population. Diabetol Metab Syndr 6(1):25
Mallat Z, Simon T, Benessiano J, Clément K, Taleb S, Wareham NJ et al (2009) Retinol-binding protein 4 and prediction of incident coronary events in healthy men and women. J Clin Endocrinol Metab 94(1):255–260
Markus HS (2004) Cerebral perfusion and stroke. J Neurol Neurosurg Psychiatry 75(3):353–361
Neidert S, Katan M, Schuetz P, Fluri F, Ernst A, Bingisser R, Kappos L, Engelter ST, Steck A, Müller B, Christ-Crain M (2011) Anterior pituitary axis hormones and outcome in acute ischaemic stroke. J Intern Med 269(4):420–432
Prentice RL, Paczesny S, Aragaki A, Amon LM, Chen L, Pitteri SJ et al (2010) Novel proteins associated with risk for coronary heart disease or stroke among postmenopausal women identified by in-depth plasma proteome profiling. Genome Med 2(7):48
Qi Q, Yu Z, Ye X, Zhao F, Huang P, Hu FB et al (2007) Elevated retinol-binding protein 4 levels are associated with metabolic syndrome in Chinese people. J Clin Endocrinol Metab 92(12):4827–4834
Quadro L, Blaner WS, Salchow DJ, Vogel S, Piantedosi R, Gouras P, Freeman S, Cosma MP, Colantuoni V, Gottesman ME (1999) Impaired retinal function and vitamin A availability in mice lacking retinol-binding protein. EMBO J 18(17):4633–4644
Rist PM, Jiménez MC, Tworoger SS, Hu FB, Manson JE, Sun Q, Rexrode KM (2018) Plasma retinol-binding protein 4 levels and the risk of ischemic stroke among women. J Stroke Cerebrovasc Dis 27(1):68–75
Sasaki M, Otani T, Kawakami M, Ishikawa SE (2010) Elevation of plasma retinol-binding protein 4 and reduction of plasma adiponectin in subjects with cerebral infarction. Metab-Clin Exp 59(4):527–532
Shearer KD, Stoney PN, Morgan PJ, McCaffery PJ (2012) A vitamin for the brain. Trends Neurosci 35(12):733–741
Sun Q, Kiernan UA, Shi L, Phillips DA, Kahn BB, Hu FB et al (2013) Plasma retinol-binding protein 4 (RBP4) levels and risk of coronary heart disease: a prospective analysis among women in the nurses’ health study. Circulation 127:1938–1947
Tang WZ, Wang XB, Li HT, Dong M, Ji X (2017) Serum copeptin predicts severity and recurrent stroke in ischemic stroke patients. Neurotox Res 32(3):420–425
Tu WJ, Ma GZ, Ni Y, Hu XS, Luo DZ, Zeng XW et al (2017a) Copeptin and NT-proBNP for prediction of all-cause and cardiovascular death in ischemic stroke. Neurology 88(20):1899–1905
Tu WJ, Zeng XW, Deng A, Zhao SJ, Luo DZ, Ma GZ., ... & Liu Q (2017b) Circulating FABP4 (fatty acid–binding protein 4) is a novel prognostic biomarker in patients with acute ischemic stroke. Stroke; 48(6): 1531–1538
Wang J, Chen H, Liu Y, Zhou W, Sun R, Xia M (2015) Retinol binding protein 4 induces mitochondrial dysfunction and vascular oxidative damage. Atherosclerosis 240(2):335–344
Yang Q, Graham TE, Mody N, Preitner F, Peroni OD, Zabolotny JM et al (2005) Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature 436(7049):356–362
Yao-Borengasser A, Varma V, Bodles AM, Rasouli N, Phanavanh B, Lee MJ et al (2007) Retinol binding protein 4 expression in humans: relationship to insulin resistance, inflammation, and response to pioglitazone. J Clin Endocrinol Metab 92(7):2590–2597
Zhang JX, Zhu GP, Zhang BL, Cheng YY (2017) Elevated serum retinol-binding protein 4 levels are correlated with blood pressure in prehypertensive Chinese. J Hum Hypertens 31(10):611–615
Ziegelmeier M, Bachmann A, Seeger J, Lossner U, Kratzsch J, Blüher M et al (2007) Serum levels of adipokine retinol-binding protein-4 in relation to renal function. Diabetes Care 30(10):2588–2592
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We express our gratitude to all the patients who participated in this study, and thereby made this work possible.
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The present study has been approved by the ethics committee of the Cangzhou Central Hospital. All participants or their relatives were informed of the study protocol and their written informed consents were obtained.
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Liu, C., Che, Y. Retinol-Binding Protein 4 Predicts Lesion Volume (Determined by MRI) and Severity of Acute Ischemic Stroke. Neurotox Res 35, 92–99 (2019). https://doi.org/10.1007/s12640-018-9933-z
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DOI: https://doi.org/10.1007/s12640-018-9933-z