Altered Expression of MicroRNA-15a and Kruppel-Like Factor 4 in Cerebrospinal Fluid and Plasma After Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Cerebral vasospasm (CVS) is a major determinant of prognosis in patients with subarachnoid hemorrhage (SAH). Alteration in the vascular phenotype contributes to development of CVS. However, little is known about the role of microRNAs (miRNAs) in the phenotypic alteration after SAH. We investigated the expression profile of miRNAs and the chronologic changes in the expression of microRNA-15a (miR-15a) and Kruppel-like factor 4 (KLF4), a potent regulator of vascular phenotype modulation that modulates the expression of miR-15a, in the plasma and cerebrospinal fluid (CSF) of patients with SAH.

METHODS: Peripheral blood and CSF samples were collected from 8 patients with aneurysmal SAH treated with endovascular obliteration. Samples obtained from 3 patients without SAH were used as controls in the analysis. Exosomal miRNAs were isolated and subjected to microarray analysis with the three-dimensional-gene miRNA microarray kit. The time course of the expression of miR-15a and KLF4 was analyzed using quantitative real-time polymerase chain reaction.

RESULTS: Microarray analysis showed that 12 miRNAs including miR-15a were upregulated or downregulated both in the CSF and in plasma after SAH within 3 days. Quantitative real-time polymerase chain reaction showed that miR-15a expression was significantly increased in both the CSF and plasma, with a peak around 3-5 days after SAH, whereas the expression of KLF4 was significantly decreased around 1-3 days after SAH and remained lower than in controls.

CONCLUSIONS: Our results suggest that an early and persistent decrease in KLF4 followed by an increase in miR-15a may contribute to the altered vascular phenotype, resulting in development of CVS.