title: Ligustrazine attenuates oxidative stress-induced activation of hepatic stellate cells by interrupting platelet-derived growth factor-β receptor-mediated ERK and p38 pathways.
abstract: Hepatic fibrosis represents a frequent event following chronic insult to trigger wound healing reactions with accumulation of extracellular matrix (ECM) in the liver. Activation of hepatic stellate cells (HSCs) is the pivotal event during liver fibrogenesis. Compelling evidence indicates that oxidative stress is concomitant with liver fibrosis irrespective of the underlying etiology. Natural antioxidant ligustrazine exhibits potent antifibrotic activities, but the mechanisms are poorly understood. Our studies were to investigate the ligustrazine effects on HSC activation stimulated by hydrogen peroxide (H(2)O(2)), an in vitro model mimicking the oxidative stress in liver fibrogenesis, and to elucidate the possible mechanisms. Our results demonstrated that H(2)O(2) at 5μM significantly stimulated HSC proliferation and expression of marker genes of HSC activation; whereas ligustrazine dose-dependently suppressed proliferation and induced apoptosis in H(2)O(2)-activated HSCs, and attenuated expression of fibrotic marker genes. Mechanistic investigations revealed that ligustrazine reduced platelet-derived growth factor-β receptor (PDGF-βR) expression and blocked the phosphorylation of extracellular regulated protein kinase (ERK) and p38 kinase, two downstream effectors of PDGF-βR. Further molecular evidence suggested that ligustrazine interruption of ERK and p38 pathways was dependent on the blockade of PDGF-βR and might be involved in ligustrazine reduction of fibrotic marker gene expression under H(2)O(2) stimulation. Furthermore, ligustrazine modulated some proteins critical for HSC activation and ECM homeostasis in H(2)O(2)-stimulated HSCs. These data collectively indicated that ligustrazine could attenuate HSC activation caused by oxidative stress, providing novel insights into ligustrazine as a therapeutic option for hepatic fibrosis.
authors.affiliation: Department of Clinical Pharmacy, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210029, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Chunyan
authors.initials: C
authors.lastname: Ni
authors.forename: Desong
authors.initials: D
authors.lastname: Kong
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhang
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Zhu
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: D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D005434:Flow Cytometry; D005819:Genetic Markers; D055166:Hepatic Stellate Cells / Q000187:drug effects*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007202:Indicators and Reagents; D008103:Liver Cirrhosis / Q000139:chemically induced* / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D011719:Pyrazines / Q000494:pharmacology*; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D017382:Reactive Oxygen Species / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects*
chemical_list: D000975:Antioxidants; D005819:Genetic Markers; D007202:Indicators and Reagents; D016877:Oxidants; D011719:Pyrazines; D017382:Reactive Oxygen Species; D012313:RNA; D006861:Hydrogen Peroxide; D020797:Receptor, Platelet-Derived Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases; C017953:tetramethylpyrazine