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Tetramethylpyrazine inhibits angiotensin II‐induced activation of hepatic stellate cells associated with interference of platelet‐derived growth factor β receptor pathways
Author(s) -
Zhang Xiaoping,
Zhang Feng,
Kong Desong,
Wu Xiafei,
Lian Naqi,
Chen Li,
Lu Yin,
Zheng Shizhong
Publication year - 2014
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.12818
Subject(s) - hepatic stellate cell , angiotensin ii , microbiology and biotechnology , platelet derived growth factor receptor , growth factor , platelet derived growth factor , cancer research , tetramethylpyrazine , chemistry , protein kinase b , pi3k/akt/mtor pathway , hepatic fibrosis , signal transduction , losartan , biology , receptor , fibrosis , endocrinology , medicine , biochemistry , pathology , alternative medicine
Liver fibrosis represents a frequent event following chronic insult to trigger wound healing responses in the liver. Activation of hepatic stellate cells ( HSC s) 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 HSC s. 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 HSC s 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.