title: Inhibition of YAP signaling contributes to senescence of hepatic stellate cells induced by tetramethylpyrazine.
abstract: Accumulating evidence indicates that hepatic stellate cells (HSCs) are the central mediators and major effectors in the development of hepatic fibrosis. It is well-known that regulation of cell proliferation and apoptosis are potential strategies to block the activation of HSCs. Recently, several studies have revealed that induction of HSC senescence could prevent and cure the liver fibrosis. In our previous work, we have demonstrated that the natural product tetramethylpyrazine (TMP) could inhibit the activation of HSCs and ameliorate hepatic fibrosis. The aim of this study was to identify a new role of TMP in the regulation of activated HSC senescence and to elucidate the underlying mechanisms. In this study, our data showed that TMP could promote HSC senescence in vivo and in vitro. Moreover, TMP affected the cell cycle and telomerase activity. We further demonstrated that P53 siRNA or P53 pharmacological inhibitor PFT-α abrogated the TMP-induced HSC senescence in vitro. Meanwhile, similar results were obtained in vivo. Further studies indicated that TMP promoted the expression of P53 through a YAP inhibition-dependent mechanism. Moreover, silencing YAP enhanced TMP induction of activated HSC senescence. Collectively, our results suggested that TMP inhibited the activation of HSCs by inducing senescence and had therapeutic implication for the treatment of liver fibrosis.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Huanhuan
authors.initials: H
authors.lastname: Jin
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Naqi
authors.initials: N
authors.lastname: Lian
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Mianli
authors.initials: M
authors.lastname: Bian
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Xingran
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Chenxi
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Chunfeng
authors.initials: C
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Hao
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Shunyu
authors.initials: S
authors.lastname: Yao
authors.affiliation: Department of Pharmacy, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Jiangjuan
authors.initials: J
authors.lastname: Shao
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Pathology, School of Medicine, Saint Louis University, MO, USA.
authors.forename: Anping
authors.initials: A
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China. Electronic address: nytws@163.com.
authors.forename: Shizhong
authors.initials: S
authors.lastname: Zheng
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000502:physiology; D000818:Animals; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000502:physiology; D018797:Cell Cycle Proteins; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D016922:Cellular Senescence / Q000187:drug effects* / Q000502:physiology; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000502:physiology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D011719:Pyrazines / Q000494:pharmacology* / Q000627:therapeutic use; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D011719:Pyrazines; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; C017953:tetramethylpyrazine
keywords: Hepatic stellate cells; P53; Senescence; Tetramethylpyrazine; Yes-associated protein