Differential expression of circulating exosomal microRNAs in refractory intracranial atherosclerosis associated with antiangiogenesis

Hao Jiang,Nestor R Gonzalez,Shlee S Song,Oana M Dumitrascu,Konrad H Schlick,Jeffrey L Saver,Jianwei Pan,Juan F Toscano,Patrick D Lyden

doi:10.1038/s41598-019-54542-y

Abstract

Intracranial atherosclerotic disease (ICAD) is a common cause of stroke with high rates of ischemic recurrence. We aimed to investigate the role of circulating exosomal microRNAs (e-miRNAs) in recurrent ischemic events in ICAD. Consecutive patients with severe ICAD undergoing intensive medical management (IMM) were prospectively enrolled. Those with recurrent ischemic events despite IMM during 6-month follow up were algorithmically matched to IMM responders. Baseline blood e-miRNA expression levels of the matched patients were measured using next generation sequencing. A total of 122 e-miRNAs were isolated from blood samples of 10 non-responders and 11 responders. Thirteen e-miRNAs predicted IMM failure with 90% sensitivity and 100% specificity. Ingenuity pathway analysis (IPA) determined 10 of the 13 e-miRNAs were significantly associated with angiogenesis-related biological functions (p < 0.025) and angiogenic factors that have been associated with recurrent ischemic events in ICAD. These e-miRNAs included miR-122-5p, miR-192-5p, miR-27b-3p, miR-16-5p, miR-486-5p, miR-30c-5p, miR-10b-5p, miR-10a-5p, miR-101-3p, and miR-24-3p. As predicted by IPA, the specific expression profiles of these 10 e-miRNAs in non-responders had a net result of inhibition of the angiogenesis-related functions and up expression of the antiangiogenic factors. This study revealed distinct expression profiles of circulating e-miRNAs in refractory ICAD, suggesting an antiangiogenic mechanism underlying IMM failure.

Highlights

Intracranial atherosclerotic disease (ICAD) is a common cause of stroke with high rates of ischemic recurrence
The present study is the first survey of intracranial atherosclerosis patients receiving intensive medical management (IMM) to associate the exosomal miRNA (e-miRNA) expression profile with recurrent ischemic events despite treatment
The occurrence of transient ischemia indicates the evolution of atherosclerosis and inefficacy of IMM and suggests upcoming stroke that may cause severe disability and death

Summary

Introduction

Intracranial atherosclerotic disease (ICAD) is a common cause of stroke with high rates of ischemic recurrence. The circulating exosomes mainly derived from the endothelium, platelet, and blood cells represent an encapsulation that protects miRNA from external ribonucleases during transportation, and enrich the majority of the detectable miRNAs in plasma to a more concentrated level and resultant stronger biological effect[17] In these terms, the circulating exosomal miRNA (e-miRNA) profile could be an optimal candidate for recognition of high-risk ICAD patients refractory to IMM. We prospectively enrolled patients diagnosed with ICAD undergoing IMM and measured the circulating e-miRNA levels at baseline and analyzed the association between e-miRNA expression profiles and recurrent ischemic events during a 6-month follow up. The biological functions and molecular targets of the outcome-related e-miRNA profiles were further investigated in the Ingenuity Pathway Analysis (IPA) environment to gain insight on the mechanisms underlying the disease progression and IMM failure in ICAD

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