Tetramethylpyrazine inhibits angiotensin II-induced activation of hepatic stellate cells associated with interference of platelet-derived growth factor β receptor pathways.

Liver fibrosis represents a frequent event following chronic insult to trigger wound healing responses in the liver. Activation of hepatic stellate cells ( HSCs) is a pivotal event during liver fibrogenesis. Compelling evidence indicates that the renin-angiotensin system ( RAS) takes part in the pathogenesis of liver fibrosis. Angiotensin II (Ang II), the primary effector peptide of the RAS, has been demonstrated to be a potent pro-fibrogenic molecule for HSC activation. In this study we investigated the effects of tetramethylpyrazine ( TMP) on HSC 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 α-smooth muscle actin (α- SMA) and α1(I) procollagen, and enhanced the invasion capacity in HSCs. TMP inhibited proliferation and arrested the cell cycle at the G2/M checkpoint associated with altering several cell cycle regulatory proteins in Ang II-treated HSCs. TMP also modulated Bcl-2 family proteins and activated the caspase cascade leading to apoptosis in Ang II-treated HSCs. Moreover, TMP reduced the expression of α- SMA and α1(I) procollagen at m RNA and protein levels, and these effects were associated with interference of the platelet-derived growth factor β receptor ( PDGF-βR) mediated PI3K/ AKT/m TOR pathway in HSCs exposed to Ang II. Furthermore, Ang II-enhanced HSC invasion capacity was diminished by TMP, which was associated with interference of PDGF-βR/ FAK signaling. These data collectively indicated that interference of PDGF-βR-mediated fibrotic pathways was involved in TMP inhibition of HSC activation caused by Ang II, providing novel mechanistic insights into TMP as a potential therapeutic remedy for hepatic fibrosis. [ABSTRACT FROM AUTHOR]