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Aging and disease    2018, Vol. 9 Issue (2) : 172-781     DOI: 10.14336/AD.2017.0602
Orginal Article |
Diagnostic and Immunosuppressive Potential of Elevated Mir-424 Levels in Circulating Immune Cells of Ischemic Stroke Patients
Li Guangwen1,2, Ma Qingfeng1, Wang Rongliang1,2, Fan Zhibin1,2, Tao Zhen1,2, Liu Ping1, Zhao Haiping1,2,*, Luo Yumin1,2,3,*
1Cerebrovascular Diseases Research Institute and Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, China
2Beijing Geriatric Medical Research Center and Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases, Beijing, China
3Beijing Institute for Brain Disorders, Beijing, China
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Abstract  

Our previous study demonstrated that microRNA-424 (miR-424) protected against experimental stroke through inhibition of microglial proliferation and activation by targeting cell cycle proteins. The purpose of this study was to further explore the clinical significance of miR-424 in peripheral immune cells of patients with acute ischemic stroke (AIS). Blood samples were collected from 40 patients within 6 hours of symptom onset and 27 control subjects. MiR-424 levels in lymphocytes, neutrophils and plasma were determined by quantitative realtime-PCR. The diagnostic sensitivity and specificity of miR-424 for stroke was evaluated by receiver operator characteristic (ROC) curve. The correlation between miR-424 levels and clinical data was analyzed using Pearson’s correlation test. Plasma levels of inflammatory mediators (TNF-α, IL-10) and neurotrophic factor (IGF-1) were detected by ELISA. Notably, miR-424 expression levels in lymphocytes and neutrophils increased after stroke, suggestive of its diagnostic value in ischemic stroke. MiR-424 levels in neutrophils were negatively correlated with infarct volume. Lymphocytic miR-424 levels were negatively correlated with the number of lymphocytes and the expression of cyclin-dependent kinase CDK6. Moreover, plasma TNF-α and IGF-1 levels increased and decreased, respectively, in stroke patients, and miR-424 levels in lymphocytes and neutrophils were both inversely correlated with plasma TNF-α, IL-10, or IGF-1 levels. In summary, miR-424 levels in peripheral immune cells has diagnostic potential for ischemic stroke, and might affect the severity of acute stroke by depressing the peripheral inflammatory response through CDK6-dependent pathway in lymphocytes or CDK6-independent pathway neutrophils.

Keywords stroke      miR-424      lymphocytes      neutrophils      CDK6      ischemia     
Corresponding Authors: Zhao Haiping,Luo Yumin   
About author:

These authors contributed equally to this work.

Issue Date: 01 April 2018
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Li Guangwen
Ma Qingfeng
Wang Rongliang
Fan Zhibin
Tao Zhen
Liu Ping
Zhao Haiping
Luo Yumin
Cite this article:   
Li Guangwen,Ma Qingfeng,Wang Rongliang, et al. Diagnostic and Immunosuppressive Potential of Elevated Mir-424 Levels in Circulating Immune Cells of Ischemic Stroke Patients[J]. Aging and disease, 2018, 9(2): 172-781.
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http://www.aginganddisease.org/EN/10.14336/AD.2017.0602     OR     http://www.aginganddisease.org/EN/Y2018/V9/I2/172
CharacteristicsAIS patients (n=40)Controls (n=27)p value
Age (years)64.6±10.362.2±12.70.374
Gender (M/F)25/1516/110.789
Hypertension, n (%)14 (35.00)8 (29.62)0.646
Diabetes, n (%)8 (20.00)4 (14.81)0.578
Hyperlipidemia, n (%)7 (17.50)4 (14.81)0.771
Table 1  Baseline characteristics of AIS patients and controls.
Figure 1.  Changes of circulating miR-424 levels and its diagnostic value in hyperacute ischemic stroke. Quantitative real-time PCR analysis of the expressions of miR-424 in (A) lymphocytes; (B) neutrophils; and (C) plasma from AIS patients within 6 hours of symptom onset (n=40) and control group (n=27). Data represent mean ± SEM. * p<0.05 compared to control; **p<0.01 compared to control. (D) The diagnostic sensitivity and specificity of miR-424 levels in lymphocytes for AIS patients (n=40) was evaluated by ROC curve. ROC= receiver operator characteristic.
MiRsCellsAUC95%CIp valueCut-off pointSensitivitySpecificity
MiR-424Lymphocytes0.6520.527-0.7770.0272.6960.6000.900
Neutrophils0.6370.512-0.7620.0451.3000.6000.733
Table 2  Diagnosis of stroke using miR-424 levels from AIS patients within 6 hours.
Figure 2.  Correlations between miR-424 levels in circulating blood and cerebral infarct volume or NIHSS score. (A) Correlation between miR-424 levels in lymphocytes, neutrophils, and plasma and cerebral infarct volume within 6 hours of symptom onset in 24 AIS patients at admission; (B) Correlation between miR-424 levels in lymphocytes and neutrophils within 6 hours and NIHSS score in 40 AIS patients at admission; (C) Correlation between miR-424 levels in lymphocytes and neutrophils within 6 hours and NIHSS score in 40 AIS patients at 7 days after therapy. AIS, acute ischemic stroke.
Figure 3.  Correlations between miR-424 levels in circulating immune cells and in plasma. (A) Correlation between plasma miR-424 levels and its levels in lymphocytes from AIS patients. (B) Correlation between plasma miR-424 levels and its levels in neutrophils from AIS patients. AIS, acute ischemic stroke. N=40.
Figure 4.  Correlations between miR-424 levels in lymphocytes and neutrophils, and the number of lymphocytes and neutrophils and CDK6 expression. (A) Correlation between miR-424 levels in lymphocytes and the number of lymphocytes from 40 AIS patients; (B) Correlation between miR-424 and CDK6 levels in lymphocytes from 19 AIS patients; (C) Correlation between miR-424 levels in neutrophils and the number of neutrophils from 40 AIS patients; (D) Correlation between miR-424 and CDK6 levels in neutrophils from 19 AIS patients. AIS, acute ischemic stroke.
Figure 5.  Correlations between changes in plasma TNF-α and IL-10 levels with miR-424 levels in lymphocytes and neutrophils. (A) TNF-α levels in plasma from 33 stroke patients and 24 control volunteers; ***p<0.001 compared to control. (B) Correlation between miR-424 levels in lymphocyte and TNF-α levels in plasma from 33 AIS patients. (C) Correlation between miR-424 levels in neutrophils and TNF-α levels in plasma from 33 AIS patients; (D) IL-10 levels in plasma from 33 stroke patients and 24 control volunteers. (E) Correlation between miR-424 levels in lymphocytes and IL-10 levels in plasma from 33 AIS patients; (F) Correlation between miR-424 levels in neutrophils and IL-10 levels in plasma from 33 AIS patients. Data represent mean±SEM. TNF-α, tumor necrosis factor-alpha; IL-10, interleukin-10. AIS, acute ischemic stroke.
Figure 6.  Correlations between change in plasma IGF1 levels with miR-424 levels in lymphocytes and neutrophils. (A) IGF1 levels in plasma from 33 stroke patients and 24 control volunteers; **p<0.01 compared to control. (B) Correlation between miR-424 levels in lymphocytes and IGF1 levels in plasma from 33 AIS patients; (C) Correlation between miR-424 levels in neutrophils and IGF1 levels in plasma from 33 AIS patients. IGF1(insulin-like growth factor 1),
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