Abstract
Brain endothelial cells (BECs) are involved in the pathogenesis of ischemic stroke. Recently, several microRNAs (miRNAs) in BECs were reported to regulate the endothelial function in ischemic brain. Therefore, modulation of miRNAs in BECs by a therapeutic oligonucleotide to inhibit miRNA (antimiR) could be a useful strategy for treating ischemic stroke. However, few attempts have been made to achieve this strategy via systemic route due to lack of efficient delivery-method toward BECs. Here, we have developed a new technology for delivering an antimiR into BECs and silencing miRNAs in BECs, using a mouse ischemic stroke model. We designed a heteroduplex oligonucleotide, comprising an antimiR against miRNA-126 (miR-126) known as the endothelial-specific miRNA and its complementary RNA, conjugated to α-tocopherol as a delivery ligand (Toc-HDO targeting miR-126). Intravenous administration of Toc-HDO targeting miR-126 remarkably suppressed miR-126 expression in ischemic brain of the model mice. In addition, we showed that Toc-HDO targeting miR-126 was delivered into BECs more efficiently than the parent antimiR in ischemic brain, and that it was delivered more effectively in ischemic brain than non-ischemic brain of this model mice. Our study highlights the potential of this technology as a new clinical therapeutic option for ischemic stroke.
Highlights
Brain endothelial cells (BECs) are involved in the pathogenesis of ischemic stroke
In the permanent middle cerebral artery occlusion (pMCAO) mouse model, intravenously administered Toc-heteroduplex oligonucleotide (HDO) with the selected a therapeutic oligonucleotide to inhibit miRNA (antimiR) #7 as the parent strand more effectively reduced miR-126 expression levels in the ischemic region compared with the single-stranded antimiR #7
We considered that Toc-HDO was delivered into the target cell at least in part by lipoprotein receptor–mediated uptake along the transport pathway of α-tocopherol after Toc-HDO bound to lipoproteins in mouse serum[15,16,29]
Summary
Brain endothelial cells (BECs) are involved in the pathogenesis of ischemic stroke. Recently, several microRNAs (miRNAs) in BECs were reported to regulate the endothelial function in ischemic brain. We designed a heteroduplex oligonucleotide, comprising an antimiR against miRNA-126 (miR-126) known as the endothelial-specific miRNA and its complementary RNA, conjugated to α-tocopherol as a delivery ligand (Toc-HDO targeting miR126). Compared with the corresponding ASO, intravenously administered Toc-conjugated HDOs (Toc-HDOs) were more effectively delivered into BECs of normal mice where they more efficiently downregulated the expression of a BEC-specific target m RNA15. It is unclear whether miRNA-targeting Toc-HDOs with an antimiR as the parent strand can be delivered into BECs and regulate miRNA in BECs under conditions of ischemic stroke
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