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Activation of hepatic stellate cells (<jats:styled-content style=\"fixed-case\">HSC<\/jats:styled-content>s) is a pivotal event during liver fibrogenesis. Compelling evidence indicates that the renin\u2010angiotensin system (<jats:styled-content style=\"fixed-case\">RAS<\/jats:styled-content>) takes part in the pathogenesis of liver fibrosis. Angiotensin II (Ang II), the primary effector peptide of the<jats:styled-content style=\"fixed-case\">RAS<\/jats:styled-content>, has been demonstrated to be a potent pro\u2010fibrogenic molecule for<jats:styled-content style=\"fixed-case\">HSC<\/jats:styled-content>activation. In this study we investigated the effects of tetramethylpyrazine (<jats:styled-content style=\"fixed-case\">TMP<\/jats:styled-content>) on<jats:styled-content style=\"fixed-case\">HSC<\/jats:styled-content>activation induced by Ang II in order to elucidate the underlying mechanisms. Our results demonstrated that Ang II significantly promoted cell growth, upregulated the expression of the fibrotic markers \u03b1\u2010smooth muscle actin (\u03b1\u2010<jats:styled-content style=\"fixed-case\">SMA<\/jats:styled-content>) and \u03b11(I) procollagen, and enhanced the invasion capacity in<jats:styled-content style=\"fixed-case\">HSC<\/jats:styled-content>s.<jats:styled-content style=\"fixed-case\">TMP<\/jats:styled-content>inhibited proliferation and arrested the cell cycle at the G2\/M checkpoint associated with altering several cell cycle regulatory proteins in Ang II\u2010treated HSCs.<jats:styled-content style=\"fixed-case\">TMP<\/jats:styled-content>also modulated Bcl\u20102 family proteins and activated the caspase cascade leading to apoptosis in Ang II\u2010treated HSCs. Moreover,<jats:styled-content style=\"fixed-case\">TMP<\/jats:styled-content>reduced the expression of \u03b1\u2010<jats:styled-content style=\"fixed-case\">SMA<\/jats:styled-content>and \u03b11(I) procollagen at m<jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content>and protein levels, and these effects were associated with interference of the platelet\u2010derived growth factor \u03b2 receptor (<jats:styled-content style=\"fixed-case\">PDGF<\/jats:styled-content>\u2010\u03b2R) mediated PI3K\/<jats:styled-content style=\"fixed-case\">AKT<\/jats:styled-content>\/m<jats:styled-content style=\"fixed-case\">TOR<\/jats:styled-content>pathway in<jats:styled-content style=\"fixed-case\">HSC<\/jats:styled-content>s exposed to Ang II. Furthermore, Ang II\u2010enhanced<jats:styled-content style=\"fixed-case\">HSC<\/jats:styled-content>invasion capacity was diminished by<jats:styled-content style=\"fixed-case\">TMP<\/jats:styled-content>, which was associated with interference of<jats:styled-content style=\"fixed-case\">PDGF<\/jats:styled-content>\u2010\u03b2R\/<jats:styled-content style=\"fixed-case\">FAK<\/jats:styled-content>signaling. These data collectively indicated that interference of<jats:styled-content style=\"fixed-case\">PDGF<\/jats:styled-content>\u2010\u03b2R\u2010mediated fibrotic pathways was involved in<jats:styled-content style=\"fixed-case\">TMP<\/jats:styled-content>inhibition of<jats:styled-content style=\"fixed-case\">HSC<\/jats:styled-content>activation caused by Ang II, providing novel mechanistic insights into<jats:styled-content style=\"fixed-case\">TMP<\/jats:styled-content>as a potential therapeutic remedy for hepatic fibrosis.<\/jats:p>","DOI":"10.1111\/febs.12818","type":"journal-article","created":{"date-parts":[[2014,4,12]],"date-time":"2014-04-12T15:36:55Z","timestamp":1397317015000},"page":"2754-2768","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Tetramethylpyrazine inhibits angiotensin II\u2010induced activation of hepatic stellate cells associated with interference of platelet\u2010derived growth factor \u03b2 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