HIV-1 Tat C Modulates Expression of miRNA-101 to Suppress VE-Cadherin in Human Brain Microvascular Endothelial Cells

摘要

HIV-1 infection leads to the development of HIV-associated neurological disorders. The HIV-1 Tat protein has been reported to exert an adverse effect on blood–brain barrier integrity and permeability. Perturbation in permeability is mainly caused by disruptions in adherens junctions and tight junction proteins. We have identified HIV-1 Tat C-induced disruption of VE-cadherin mediated by miRNA-101 in human brain microvascular endothelial cells (BMVECs). HIV-1 Tat C increased the expression of miR-101, which led to downregulation of VE-cadherin. Overexpression of miR-101 resulted into the suppression of VE-cadherin. Inhibition of miR-101 by the miRNA inhibitor enhanced the expression of VE-cadherin. We have demonstrated that VE-cadherin is a direct target of miR-101 using a luciferase reporter assay, which showed that mutated VE-cadherin 3′UTR and miR-101 cotransfection did not change luciferase activity. By overexpression and knockdown of miR-101, we have demonstrated that the expression level of claudin-5 is governed by the expression of VE-cadherin. These findings demonstrate a novel mechanism for the regulation of barrier permeability by miR-101 via posttranscriptional regulation of VE-cadherin in human BMVECs exposed to the HIV-1 Tat C protein.