PMID- 23792773
OWN - NLM
STAT- MEDLINE
DCOM- 20150807
LR  - 20181202
IS  - 1873-4596 (Electronic)
IS  - 0891-5849 (Linking)
VI  - 65
DP  - 2013 Dec
TI  - Signaling pathways involved in isoprostane-mediated fibrogenic effects in rat 
      hepatic stellate cells.
PG  - 201-207
LID - S0891-5849(13)00304-3 [pii]
LID - 10.1016/j.freeradbiomed.2013.06.023 [doi]
AB  - Despite evidence supporting a potential role for F2-isoprostanes (F2-IsoP's) in 
      liver fibrosis, their signaling mechanisms are poorly understood. We have 
      previously provided evidence that F2-IsoP's stimulate hepatic stellate cell (HSC) 
      proliferation and collagen hyperproduction by activation of a modified form of 
      isoprostane receptor homologous to the classic thromboxane receptor (TP). In this 
      paper, we examined which signal transduction pathways are set into motion by 
      F2-IsoP's to exert their fibrogenic effects. HSCs were isolated from rat liver, 
      cultured to their activated myofibroblast-like phenotype, and then treated with 
      the isoprostane 15-F2t-isoprostane (15-F2t-IsoP). Inositol trisphosphate (IP3) 
      and adenosine 3',5'-cyclic monophosphate (cAMP) levels were determined using 
      commercial kits. Mitogen-activated protein kinase (MAPK) and cyclin D1 expression 
      was assessed by Western blotting. Cell proliferation and collagen synthesis were 
      determined by measuring [(3)H]thymidine and [(3)H]proline incorporation, 
      respectively. 15-F2t-IsoP elicited an activation of 
      extracellular-signal-regulated kinase (ERK), p38 MAPK, and c-Jun NH2-terminal 
      kinase (JNK), which are known to be also regulated by G-protein-coupled 
      receptors. Preincubation with specific ERK (PD98059), p38 (SB203580), or JNK 
      (SP600125) inhibitors prevented 15-F2t-IsoP-induced cell proliferation and 
      collagen synthesis. 15-F2t-IsoP decreased cAMP levels within 30 min, suggesting 
      binding to the TPbeta isoform and activation of Gialpha protein. Also, 15-F2t-IsoP 
      increased IP3 levels within a few minutes, suggesting that the Gq protein pathway 
      is also involved. In conclusion, the fibrogenic effects of F2-IsoP's in HSCs are 
      mediated by downstream activation of MAPKs, through TP binding that couples via 
      both Gqalpha and Gialpha proteins. Targeting TP receptor, or its downstream pathways, may 
      contribute to preventing oxidative damage in liver fibrosis.
CI  - Copyright (c) 2013 Elsevier Inc. All rights reserved.
FAU - Acquaviva, Alessandra
AU  - Acquaviva A
AD  - Department of Molecular and Developmental Medicine, University of Siena, I-53100 
      Siena, Italy.
FAU - Vecchio, Daniela
AU  - Vecchio D
AD  - Department of Molecular and Developmental Medicine, University of Siena, I-53100 
      Siena, Italy.
FAU - Arezzini, Beatrice
AU  - Arezzini B
AD  - Department of Molecular and Developmental Medicine, University of Siena, I-53100 
      Siena, Italy.
FAU - Comporti, Mario
AU  - Comporti M
AD  - Department of Molecular and Developmental Medicine, University of Siena, I-53100 
      Siena, Italy.
FAU - Gardi, Concetta
AU  - Gardi C
AD  - Department of Molecular and Developmental Medicine, University of Siena, I-53100 
      Siena, Italy. Electronic address: concetta.gardi@unisi.it.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130620
PL  - United States
TA  - Free Radic Biol Med
JT  - Free radical biology & medicine
JID - 8709159
RN  - 0 (Isoprostanes)
RN  - 0 (Receptors, Thromboxane)
RN  - 27415-26-5 (8-epi-prostaglandin F2alpha)
RN  - B7IN85G1HY (Dinoprost)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Cells, Cultured
MH  - Dinoprost/analogs & derivatives
MH  - Hepatic Stellate Cells/*metabolism
MH  - Isoprostanes/*metabolism/pharmacology
MH  - Liver Cirrhosis/metabolism
MH  - Rats
MH  - Receptors, Thromboxane/metabolism
MH  - Signal Transduction/*physiology
OTO - NOTNLM
OT  - 15-F2t-IsoP
OT  - AC
OT  - Collagen synthesis
OT  - DMEM
OT  - Dulbecco's modified Eagle's medium
OT  - ERK
OT  - F2-IsoP
OT  - F2-isoprostane
OT  - FSK
OT  - Free radicals
OT  - HSC
OT  - I-BOP
OT  - IP(3)
OT  - Isoprostane receptor
OT  - JNK
OT  - Liver fibrosis
OT  - MAPK
OT  - PKA
OT  - PKC
OT  - PLC
OT  - TCA
OT  - TP
OT  - [1S-[1alpha,2alpha(Z),3beta(1E,3S*),4alpha]]-7-[3-[3-hydroxy-4-(4-iodophenoxy)-1-butenyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic 
      acid
OT  - adenosine 3',5'-cyclic monophosphate
OT  - adenylyl cyclase
OT  - c-Jun NH(2)-terminal kinase
OT  - cAMP
OT  - extracellular-signal-regulated kinase
OT  - forskolin
OT  - hepatic stellate cell
OT  - inositol trisphosphate
OT  - mitogen-activated protein kinases
OT  - phospholipase C
OT  - protein kinase A
OT  - protein kinase C
OT  - thromboxane A2 receptor
OT  - trichloroacetic acid
EDAT- 2013/06/25 06:00
MHDA- 2015/08/08 06:00
CRDT- 2013/06/25 06:00
PHST- 2013/02/20 00:00 [received]
PHST- 2013/06/06 00:00 [revised]
PHST- 2013/06/12 00:00 [accepted]
PHST- 2013/06/25 06:00 [entrez]
PHST- 2013/06/25 06:00 [pubmed]
PHST- 2015/08/08 06:00 [medline]
AID - S0891-5849(13)00304-3 [pii]
AID - 10.1016/j.freeradbiomed.2013.06.023 [doi]
PST - ppublish
SO  - Free Radic Biol Med. 2013 Dec;65:201-207. doi: 
      10.1016/j.freeradbiomed.2013.06.023. Epub 2013 Jun 20.