Regulation of IRS-1, insulin signaling and glucose uptake by miR-143/145 in vascular smooth muscle cells.

Regulation of insulin signaling by microRNAs in smooth muscle cells may contribute to diabetic vascular disease. The two smooth muscle enriched miRNAs miR-143 and miR-145 have been reported to target mediators of insulin signaling in non-smooth muscle cells. In this study, we aimed to determine the importance of this regulation in vascular smooth muscle cells, where expression of miR-143/145 is much higher than in other cell types. Smooth muscle cells deficient of the miR-143/145 cluster were used, as well as smooth muscle cells transfected with mimics/inhibitors for either miR-143 or miR-145. We found that deletion of miR-143/145 in smooth muscle results in a dramatic upregulation IRS-1 expression and insulin signaling, and an increased insulin-induced glucose uptake. Furthermore, specific modulation of either miR-145 or miR-143 expression regulated specific targets (IRS-1, ORP8 and the IGF-1 receptor) in the insulin signaling pathway. Consequently, transient inhibition or overexpression of either miR-143 or miR-145 was sufficient to regulate insulin signaling in smooth muscle cells. In conclusion, the results of this study support an important role for both miR-143 and miR-145 in the regulation of insulin signaling and glucose uptake in vascular smooth muscle cells.