title: Simvastatin suppresses the proangiogenic microenvironment of human hepatic stellate cells via the Kruppel-like factor 2 pathway.
abstract: OBJECTIVE
  Statins are reported to have a beneficial effect on portal hypertension (PTH); however, the exact mechanism remains unknown. Hepatic stellate cells (HSCs) can be activated by transforming growth factor beta (TGFâ) and play an important role in angiogenesis leading to PTH. Statins potently stimulate the transcription factor, Kruppel-like factor 2 (KLF2), which can negatively regulate angiogenesis. Our present study aimed to investigate the anti-angiogenic potential of statins in HSCs through the KLF2 pathway.
  
  
  METHODS
  TGFâ-induced human HSCs were exposed to simvastatin. Cell viability and proliferation were determined by MTT and BrdU-proliferation assays, respectively. Cell migration was investigated using a transwell and wound-healing assays. Gene quantification was measured by real-time polymerase chain reaction. Protein expression was detected by western blot analysis and immunohistochemistry. Inflammatory factors were measured using enzyme-linked immunosorbent assays.
  
  
  RESULTS
  Simvastatin was found to reduced cell migration and proliferation and inhibit expression of alpha smooth muscle actin in TGFâ-induced HSCs. Furthermore, simvastatin promoted already increased mRNA and protein levels of KLF2 in TGFâ-induced HSCs. In accordance with KLF2 overexpression, simvastatin increased production of endothelial nitric oxide synthesis (eNOS) and downregulated expression of some proangiogenic proteins, such as vascular endothelial growth factor, hypoxia inducible factor-1a and nuclear factor-kappa B in TGFâ-induced HSCs. At the same time, secretion of interferon-gamma increased in TGFâ induced HSCs, which was decreased by simultaneous addition of simvastatin.
  
  
  CONCLUSIONS
  Simvastatin suppressed the proangiogenic environment of HSCs activated by TGFâ, and KLF2 pathway is involved in the course.
authors: Qing
authors: Q
authors: Miao
authors: Xiaoqing
authors: X
authors: Zeng
authors: Guifen
authors: G
authors: Ma
authors: Na
authors: N
authors: Li
authors: Yimei
authors: Y
authors: Liu
authors: Tiancheng
authors: T
authors: Luo
authors: Jingjing
authors: J
authors: Lian
authors: Shiyao
authors: S
authors: Chen
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D060888:Real-Time Polymerase Chain Reaction; D019821:Simvastatin / Q000494:pharmacology*
chemical_list: D015415:Biomarkers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; D019821:Simvastatin