title: MiR-132 inhibits expression of SIRT1 and induces pro-inflammatory processes of vascular endothelial inflammation through blockade of the SREBP-1c metabolic pathway.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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 α (TNFα). The effects of miR-132 on pro-inflammatory processes, proliferation and apoptosis were assessed.
  
  
  RESULTS
  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-α, and inhibited its proliferation, viability and migration.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cardiology, The first Affiliated Hospital of Chinese PLA General Hospital, Beijing, 100048, China.
authors.forename: Liwei
authors.initials: L
authors.lastname: Zhang
authors.forename: Dangsheng
authors.initials: D
authors.lastname: Huang
authors.forename: Qiushuang
authors.initials: Q
authors.lastname: Wang
authors.forename: Dong
authors.initials: D
authors.lastname: Shen
authors.forename: Yumei
authors.initials: Y
authors.lastname: Wang
authors.forename: Bingyang
authors.initials: B
authors.lastname: Chen
authors.forename: Jinqian
authors.initials: J
authors.lastname: Zhang
authors.forename: Luyue
authors.initials: L
authors.lastname: Gai
mesh_terms: D017209:Apoptosis; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D050155:Lipogenesis / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha
chemical_list: C547077:MIRN132 microRNA, human; D035683:MicroRNAs; D051780:Sterol Regulatory Element Binding Protein 1; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C447939:SIRT1 protein, human; D056564:Sirtuin 1