MicroRNA-125a-mediated regulation of the mevalonate signaling pathway contributes to high glucose-induced proliferation and migration of vascular smooth muscle cells

摘要

Hyperglycemia contributes to the excessive proliferation and migration of vascular smooth muscle cells (VSMC), which are closely associated with atherosclerosis. MicroRNAs (miRNAs/miRs) constitute a novel class of gene regulators, which have important roles in various pathological conditions. The aim of the present study was to identify miRNAs involved in the high glucose (HG)-induced VSMC phenotype switch, and to investigate the underlying mechanism. miRNA sequencing and reverse transcription-quantitative PCR results indicated that inhibition of miR-125a expression increased the migration and proliferation of VSMCs following HG exposure, whereas the overexpression of miR-125a abrogated this effect. Furthermore, dual-luciferase reporter assay results identified that 3-hydroxy-3-methyglutaryl-coA reductase (HMGCR), one of the key enzymes in the mevalonate signaling pathway, is a target of miR-125a. Moreover, HMGCR knockdown, similarly to miR-125a overexpression, suppressed HG-induced VSMC proliferation and migration. These results were consistent with those from the miRNA target prediction programs. Using a rat model of streptozotocin-induced diabetes mellitus, it was demonstrated that miR-125a expression was gradually downregulated, and that the expressions of key enzymes in the mevalonate signaling pathway in the aortic media were dysregulated after several weeks. In addition, it was found that HG-induced excessive activation of the mevalonate signaling pathway in VSMCs was suppressed following transfection with a miR-125a mimic. Therefore, the present results suggest that decreased miR-125a expression contributed to HG-induced VSMC proliferation and migration via the upregulation of HMGCR expression. Thus, miR-125a-mediated regulation of the mevalonate signaling pathway may be associated with atherosclerosis.