title: Let-7g improves multiple endothelial functions through targeting transforming growth factor-beta and SIRT-1 signaling.
abstract: OBJECTIVE
  The present study aimed to explore the role of microribonucleic acid (miRNA) Let-7g in regulating endothelial functions.
  
  
  BACKGROUND
  Derangement of miRNAs is implicated in the pathogenesis of cardiovascular diseases. Because the transforming growth factor (TGF)-β pathway plays a regulatory role in endothelial functions, miRNAs targeted at TGF-β signal cascade might affect vascular health.
  
  
  METHODS
  Bioinformatics software predicted that Let-7g can influence the TGF-β pathway by targeting 3 genes. The Let-7g's effects on multiple endothelial functions were first tested in endothelial cells (ECs) and then in apolipoprotein E knockout mice. Blood samples from lacunar stroke patients were also examined to further support Let-7g's effects on human subjects.
  
  
  RESULTS
  Let-7g was experimentally confirmed to knock down the THBS1, TGFBR1, and SMAD2 genes in the TGF-β pathway. PAI-I, one of the downstream effectors of the TGF-β pathway, was also down-regulated by Let-7g. Let-7g decreased EC inflammation and monocyte adhesion and increased angiogenesis via the TGF-β pathway. Furthermore, Let-7g reduced EC senescence through increasing SIRT-1 protein. Venous injection of Let-7g inhibitor into apolipoprotein E knockout mice caused overgrowth of vascular intima-media, overexpression of PAI-1, increased macrophage infiltration, and up-regulation of TGF-β downstream genes in the carotid arteries. Let-7g's beneficial effects on EC were reduced, whereas the TGF-β pathway was suppressed by ribonucleic acid interference. Restoration of the TGF-β pathway also attenuated the effects of Let-7g overexpression. Low serum levels of Let-7g were associated with increased circulating PAI-1 levels.
  
  
  CONCLUSIONS
  Decreased Let-7g levels impair endothelial function and increase the risks of cardiovascular diseases through targeting TGF-β and SIRT-1 signaling.
authors.affiliation: Section of Neurology, Taichung Veterans General Hospital, Taichung, Taiwan; Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Yi-Chu
authors.initials: YC
authors.lastname: Liao
authors.affiliation: Department of Genome Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yung-Song
authors.initials: YS
authors.lastname: Wang
authors.affiliation: Neuroscience Laboratory, Department of Neurology, China Medical University Hospital, Taichung, Taiwan; School of Medicine, Medical College, China Medical University, Taichung, Taiwan.
authors.forename: Yuh-Cherng
authors.initials: YC
authors.lastname: Guo
authors.affiliation: Department of Genome Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Wen-Lien
authors.initials: WL
authors.lastname: Lin
authors.affiliation: Section of Neurology, Taichung Veterans General Hospital, Taichung, Taiwan; Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Ming-Hung
authors.initials: MH
authors.lastname: Chang
authors.affiliation: Department of Genome Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Medical Research and Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. Electronic address: hjuo@kmu.edu.tw.
authors.forename: Suh-Hang Hank
authors.initials: SH
authors.lastname: Juo
mesh_terms: D000818:Animals; D002318:Cardiovascular Diseases / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics*; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000096:biosynthesis / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics*; D014664:Vasodilation / Q000235:genetics*
chemical_list: D035683:MicroRNAs; D016212:Transforming Growth Factor beta; C542687:mirnlet7 microRNA, mouse; D012313:RNA; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: Let-7g; PAI-1; SIRT-1; TGF-β pathway; endothelial function