MiR-132Inhibits Expression Of SIRT1and Induces Vascular Endothelial Inflammation Through Regulation Of The SREBP-1c Metabolic Pathway

Background: Inflammation participates mainly in all stages ofatherosclerosis (AS), which begins with inflammatory changes in the endothelium,related to lipid metabolism. MicroRNA (miRNA or miR) inhibition ofinflammation related to SIRT1has been shown to be a promising therapeuticapproach for AS. However, the mechanism was still unknown. Objective: Thisstudy investigates the pathogenesis of atherosclerosis about miR-132inhibitingmetabolic pathway related to SIRT1and SREBP-1c, and inducing inflammationof Human umbilical vein endothelial cells (HUVECs). Methods: HUVECs weretransfected with miR-132mimics and inhibitors, and then treated with or withouttumor necrosis factor α (TNFα). The effects of miR-132on inflammation,proliferation and apoptosis were assessed. Results: We identified that the relative3’ UTR luciferase activities of SIRT1were significantly decreased in miR-132transfected HUVECs (0.338±0.036) compared to control (P=0.000). ThemiR-132inhibited the expression of mRNAs in HUVECs (0.53±0.06)(P＜0.01)as well as proteins of SIRT1. Expression of SREBP, fatty acid synthase (FASN)and3-hydroxy-3-methylglutaryl CoA reductase (HMGCR), which aredownstream regulated genes, was decreased in mRNA and protein levels ofHUVECs by miR-132. MiR-132promoted inflammation response and apoptosisof HUVECs induced by TNFα, and inhibited its proliferation, viability andmigration. Conclusions: SIRT1mRNAs are direct targets of miR-132. MiR-132control lipogenesis and cholesterogenesis on HUVECs by inhibiting SIRT1andSREBP-1c expression and downregulating their targeted genes, including FASNand HMGCR. Inhibition of SIRT1by miR-132was associated to lipidmetabolism-dependent inflammation of HUVECs. The newly identified miRNAs,miR-132represents a novel targeting mechanism for AS therapy.