title: Tetramethylpyrazine inhibits angiotensin II-induced activation of hepatic stellate cells associated with interference of platelet-derived growth factor β receptor pathways.
abstract: 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 mRNA and protein levels, and these effects were associated with interference of the platelet-derived growth factor β receptor (PDGF-βR) mediated PI3K/AKT/mTOR 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.
authors.affiliation: School of Hanlin, Nanjing University of Chinese Medicine, Taizhou, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhang
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Desong
authors.initials: D
authors.lastname: Kong
authors.forename: Xiafei
authors.initials: X
authors.lastname: Wu
authors.forename: Naqi
authors.initials: N
authors.lastname: Lian
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Yin
authors.initials: Y
authors.lastname: Lu
authors.forename: Shizhong
authors.initials: S
authors.lastname: Zheng
mesh_terms: D000804:Angiotensin II / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005434:Flow Cytometry; D016195:G2 Phase / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000804:Angiotensin II; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011719:Pyrazines; D020797:Receptor, Platelet-Derived Growth Factor beta; D058570:TOR Serine-Threonine Kinases; C546845:mTOR protein, rat; C017953:tetramethylpyrazine
keywords: angiotensin II; hepatic fibrosis; hepatic stellate cell; platelet-derived growth factor β receptor; tetramethylpyrazine