The Relationship Between MiR-146a?miR-21 In Plasma Of Patients With Acute Ischemic Stroke And Hemorrhagic Transformation Following Thrombolytic Therapy

ObjectiveIntravenous recombinant tissue plasminogen activator(rt-PA)is now the most effective way to treat acute ischemic stroke(AIS),but also increases the risk of hemorrhagaic transformation(HT)which restricts the application of rt-PA in the therapy of AIS.The etiology and pathophysiology of HT following thrombolysis is complex.The underlying mechanisms are likely related to the increased permeability of blood-brain barrier(BBB)and ischemia reperfusion.The purpose was to investigate the relationship between the expression levels of miR-146a?miR-21,which involved in the regulation of the permeability of BBB,in plasma of patients with AIS and HT following thrombolytic therapy.MethodsFourty patients with AIS received thrombolytic therapy using rt-PA at the Department of Neurology in the First Affiliated Hospital of Xi,an Medical University from April 2015 to October 2016 were included in the study,three patients had HT,others no HT.Using fluorescent real-time quantitative PCR to detect the expression levels of miR-146a?miR-21 in plasma before thrombolytic therapy,and collecting related clinical indicators of AIS patients.To analyse the correlation of NIHSS score?mRS score and clinical indicators.Then investigate the difference of the expression levels of miR-146a?miR-21 in different severity groups,in different prognosis groups,in HT group and non HT group.Furtherly analyse the correlation of clinical indicators in HT group and non HT group,and the correlation of the expression levels of miR-146a?miR-21 and clinical indicators in non HT group.The continuous variables normality was tested by K-S test method,the distribution of normal variables was expressed with the average and standard deviation(X ± S).Kruskal Wallis test and Mann-Whitney U test was employed to test skewed or unequal variance among two or more groups.Correlation analysis using Pearson product moment correlation or Spearman rank correlation analysis.A chi-square test was used for the comparision of Categorical variables.Results1.NIHSS score was positively correlated with mRS score(r = 0.682,P < 0.001),the expression levels of miR-21(r = 0.784,P < 0.001),and negatively correlated with the expression levels of miR-146a(r =-0.745,P < 0.001);mRS score was positively correlated with blood glucose(r = 0.530,P < 0.001),age(r = 0.469,P = 0.009),the expression levels of miR-21(r = 0.704,P < 0.001),and negatively correlated with the expression levels of miR-146a(r =-0632,P < 0.001);2.We foung that there was a significant differences in the expression levels of miR-146a?miR-21 among mild(2.03 ± 0.76,0.28 ± 0.19),moderate(1.17 ± 0.25,0.63 ± 0.24)and severe(0.72 ± 0.07,1.22 ± 0.32)AIS groups(P < 0.001,respectively).The expression levels of miR-146 a was found to be significant higher in mild AIS group when compared to moderate?severe AIS group,and significant higher in moderate AIS group when compared to severe AIS group(P < 0.017,respectively).The expression levels of miR-21 was found to be significant lower in mild AIS group when compared to moderate,severe AIS group,and significant lower in moderate AIS group when compared to severe AIS group(P < 0.017,respectively);3.The expression levels of miR-146 a in good prognosis group(1.96 ± 0.76)was significant higher than poor prognosis group(1.10 ± 0.38)(P < 0.001),The expression levels of miR-21 in good prognosis group(0.28 ± 0.13)was significant lower than poor prognosis group(0.77 ± 0.38)(P < 0.001);4.Age in HT group(79.67 ± 1.53 year)was was significant higher than non HT group(67.41 ± 11.31 year)(P < 0.05),blood glucose in HT group(9.88 ± 4.16 mmol/L)was also significant higher than non HT group(6.50 ± 2.13 mmol/L)(P < 0.05);HT was related to the mRS score(?2 = 1.926,P = 0.046);5.The expression levels of miR-146 a in HT group(0.75 ± 0.28)was significant lower than non HT group(1.64 ± 0.74)(P < 0.005),the expression levels of miR-21 in HT group(1.32 ± 0.34)was significant higher than non HT group(0.44 ± 0.28)(P < 0.05);6.The expression levels of miR-146 a was negatively correlated with history of stroke(r =-0.384,P < 0.05),history of atrial fibrillation(r =-0.493,P < 0.05)and history of the use of antiplatelet drugs(r =-0.407,P < 0.05)in non HT group;the expression levels of miR-21 was positively correlated with hypertension(r = 0.377,P < 0.05)in non HT group;7.We found that the expression levels of miR-146 a in patients without history of stroke(1.75 ± 0.58),without history of atrial fibrillation was(1.80 ± 0.78)and without history of use of antiplatelet drugs(1.78 ± 0.59)was significant higher than patients with history of stroke(0.44 ± 0.28),with history of atrial fibrillation(1.21 ± 0.36),and with history of use of antiplatelet drugs(1.42 ± 0.91)(P = 0.021,0.008,0.015,respectively)in non HT group;8.We foung that there was a significant differences in the expression levels of miR-21 among patients without hypertension(0.32 ± 0.13),patients of grade 1 hypertension(0.13 ± 0.04),patients of grade 2 hypertension(0.54 ± 0.37),patients of grade 3 hypertension(0.58 ± 0.31)(P = 0.025).And the expression levels of miR-21 was significant higher in patients of grade 3 hypertensive than patients without hypertension(P = 0.0076)in non HT group.Conclusions1.The higher of the age and blood glucose of AIS patients before rt-PA thrombolytic therapy,the greater of the risk of HT following thrombolysis;2.The expression levels of miR-146 a and miR-21 in the plasma of patients with AIS before rt-PA thrombolytic therapy can reflect the severity of AIS before thrombolysis and predict the prognosis of patients with AIS.Moreover,it had a significantly difference in HT group and non HT group,which is expected to become a potential biomarkers to predict the risk of HT following rt-PA intravenous thrombolytic therapy in patients with AIS.