MiR-135a promotes inflammatory responses of vascular smooth muscle cells from db/db mice via downregulation of FOXO1

Abstract

It has been shown that microRNAs (miRNAs) greatly affect the functions of vascular smooth muscle cells (VSMC), but the effects of mRNAs under diabetic conditions remain unclear. Using a model of diabetic db/db mice, we studied the functions of microRNA-135a (miR-135a) during VSMC dysfunction. Compared to control WT mice, miR-135a expression in VSMC was significantly increased while the level of forkhead box O1 (FOXO1) protein decreased significantly. After transfecting miR-135a mimics into VSMC, the expression of FOXO1 was decreased, while cyclooxygenase-2 (COX-2) and monocyte chemoattractant protein-1 (MCP-1) expression levels were increased, thus promoting the interaction between monocytes and WT VSMC. On the other hand, transfection of an miR-135a inhibitor reversed the activated interaction between monocytes and db/db VSMC. The pro-inflammatory responses could also be enhanced by using siRNAs to silence the FOXO1 gene in WT VSMC, suggesting a negative regulatory role of FOXO1. FOXO1 siRNAs and miR-135a mimics could both enhance the transcriptional activity of COX-2 promoter. Using chromatin immunoprecipitation, we found that in db/db VSMC, the occupancy in promoter regions of inflammatory genes by FOXO1 was reduced. miR-135a increased the inflammatory responses of VSMC involved in complications of vascular diseases by downregulating the expression of FOXO1.