Simvastatin suppresses the proangiogenic microenvironment of human hepatic stellate cells via the Kruppel-like factor 2 pathway

Background and aims: 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 (TGFβ) 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. Method: TGFβ-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. Result: Simvastatin was found to reduced cell migration and proliferation and inhibit expression of alpha smooth muscle actin in TGFβ-induced HSCs. Furthermore, simvastatin promoted already increased mRNA and protein levels of KLF2 in TGFβ-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 TGFβ-induced HSCs. At the same time, secretion of interferon-gamma increased in TGFβ induced HSCs, which was decreased by simultaneous addition of simvastatin. Conclusion: Simvastatin suppressed the proangiogenic environment of HSCs activated by TGFβ, and KLF2 pathway is involved in the course.

Bibliographic Details

Main Authors:	Miao,Qing, Zeng,Xiaoqing, Ma,Guifen, Li,Na, Liu,Yimei, Luo,Tiancheng, Lian,Jingjing, Chen,Shiyao
Format:	Digital revista
Language:	English
Published:	Sociedad Española de Patología Digestiva 2015
Online Access:	http://scielo.isciii.es/scielo.php?script=sci_arttext&pid=S1130-01082015000200002
Tags:	Add Tag No Tags, Be the first to tag this record!