MiR-132 Inhibits Expression of SIRT1 and Induces Pro-inflammatory Processes of Vascular Endothelial Inflammation through Blockade of the SREBP-1c Metabolic Pathway

Inflammation participates centrally in all stages of atherosclerosis (AS), which begins with pro-inflammatory processes and inflammatory changes in the endothelium, related to lipid metabolism. MicroRNA (miRNA) inhibition of inflammation related to SIRT1 has been shown to be a promising therapeutic approach for AS. However, the mechanism of action is unknown. We investigated whether miRNAs regulate the SIRT1 and its downstream SREBP-lipogenesis-cholesterogenesis metabolic pathway in human umbilical vein endothelial cells (HUVECs). HUVECs were transfected with miR-132 mimics and inhibitors, and then treated with or without tumor necrosis factor alpha (TNF alpha). The effects of miR-132 on pro-inflammatory processes, proliferation and apoptosis were assessed. We identified that the relative 3' UTR luciferase activities of SIRT1 were significantly decreased in miR-132 transfected HUVECs (0.338 +/- 0.036) compared to control (P = 0.000). miR-132 inhibited SIRT1 expression of mRNA level in HUVECs (0.53 +/- 0.06) (P < 0.01) as well as proteins of SIRT1. mRNA expression and protein levels of SREBP (0.45 +/- 0.07), fatty acid synthase (FASN) (0.55 +/- 0.09) and 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR) (0.62 +/- 0.08) (P < 0.01), which are downstream regulated genes, were reduced in HUVECs by miR-132. MiR-132 promoted pro-inflammatory processes and apoptosis of HUVECs induced by TNF-alpha, and inhibited its proliferation, viability and migration. SIRT1 mRNAs are direct targets of miR-132. miR-132 controls lipogenesis and cholesterogenesis in HUVECs by inhibiting SIRT1 and SREBP-1c expression and their downstream regulated genes, including FASN and HMGCR. Inhibition of SIRT1 by miR-132 was associated with lipid metabolism-dependent pro-inflammatory processes in HUVECs. The newly identified miRNA, miR-132 represents a novel targeting mechanism for AS therapy.