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

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• 作者：Liwei Zhang (1)
  Dangsheng Huang (1)
  Qiushuang Wang (1)
  Dong Shen (1)
  Yumei Wang (1)
  Bingyang Chen (1)
  Jinqian Zhang (2)
  Luyue Gai (3)
  
• 关键词：MicroRNA ; SIRT1 ; Inflammation ; SREBP ; 1c ; Lipid metabolism ; Atherosclerosis
• 刊名：Cardiovascular Drugs and Therapy
• 出版年：2014
• 出版时间：August 2014
• 年：2014
• 卷：28
• 期：4
• 页码：303-311
• 全文大小：919 KB
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• 作者单位：Liwei Zhang (1)
  Dangsheng Huang (1)
  Qiushuang Wang (1)
  Dong Shen (1)
  Yumei Wang (1)
  Bingyang Chen (1)
  Jinqian Zhang (2)
  Luyue Gai (3)
  
  1. Department of Cardiology, The first Affiliated Hospital of Chinese PLA General Hospital, Beijing, 100048, China
  2. Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China
  3. Department of Cardiology, Division of Medicine, Chinese PLA General Hospital, Beijing, 100853, China
  
• ISSN：1573-7241

文摘

Purpose 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?±-.036) compared to control (P--.000). miR-132 inhibited SIRT1 expression of mRNA level in HUVECs (0.53?±-.06) (P--.01) as well as proteins of SIRT1. mRNA expression and protein levels of SREBP (0.45?±-.07), fatty acid synthase (FASN) (0.55?±-.09) and 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR) (0.62?±-.08) (P--.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.