P5177Expressions of miR-146a induces CXCL8 maturation and is associated with aortic-related events in patients with type B acute aortic dissection

Abstract

Background: Although type B acute aortic dissection (AAD) is generally more benign and is treated with medical management for high blood pressure and intolerant pain, a substantial proportion of patients with AAD occur aortic-related adverse events including aortic rupture, aortic enlargement and retrograde type A aortic dissection. A recent experimental report has demonstrated that a member of the CXC chemokine family, CXCL8, triggered neutrophil activation and might be associated to aortic expansion and rupture after AAD. The aim of this study was to investigate CXCL8 and its related microRNA expressions in patients with AAD. Method(s): This study included 72 patients with type B AAD (mean age, 69.8+/-15.2; %male, 83%) and 66 controls with non-dilated ascending aorta (mean age, 68.7+/-12.2; %male, 82%). CXCL8 related microRNA (miR) screening in isolated peripheral blood mononuclear cells (PBMC) was performed using microarray assay for 1,700 human microRNAs. The candidate microRNAs were verified with real-time PCR. Serum levels of soluble CXCL8 measured using ELISA. Result(s): The microarray assay showed significant differences in five CXCL8 related microRNAs (miR-145, miR-146a, miR-155, miR-31, let-7i, all P<0.01). Real-time PCR verified that miR-146a was lower in AAD group versus controls (2.45+/-1.23 vs. 4.61+/-3.22, P<0.01). Serum levels of CXCL8 were higher in AAD group than in controls (23.4+/-6.2 pg / mL vs. 11.3+/-5.3 pg / mL, P<0.01). There was a weak negative correlation between miR-146a and CXCL8 levels in all subjects (r=0.37, P<0.05). Our functional approaches showed that transfection of miR-23a into isolated PBMC resulted in regulation of CXCL8 expression. After a mean follow-up of 689 days (range, 358 to 992 days), 12 patients had aorticrelated adverse events including 3 aortic-related death due to aortic rupture, 5 aortic enlargement and 4 retrograde type A aortic dissection. There were no significant differences in baseline characteristics of patients with AAD between survivors and nonsurvivors. When patients were divided into two subgroups according to median value of miR-146a and CXCL8, the number of aortic-related adverse events was significant higher in the subgroup with low miR-146a and high CXCL8 levels (all P<0.01). Multivariate analysis showed that levels of miR- 146a (RR 3.8, 95% CI 1.9 - 7.9) were a strong predictor of aortic-related adverse events after adjustment for baseline characteristics. Conclusion(s): The present study suggested that downregulated miR-146a is involved in the progression of AAD via CXCL8 maturation, and may provide important prognostic information in patients with AAD.