PMID- 24961950
OWN - NLM
STAT- MEDLINE
DCOM- 20151026
LR  - 20211203
IS  - 1573-4919 (Electronic)
IS  - 0300-8177 (Linking)
VI  - 394
IP  - 1-2
DP  - 2014 Sep
TI  - Endoplasmic reticulum stress-induced hepatic stellate cell apoptosis through 
      calcium-mediated JNK/P38 MAPK and Calpain/Caspase-12 pathways.
PG  - 1-12
LID - 10.1007/s11010-014-2073-8 [doi]
AB  - Recent reports considered that it was the disturbance of calcium homeostasis and 
      the accumulation of misfolded proteins in the endoplasmic reticulum (ER) that 
      activated hepatic stellate cells (HSCs) apoptosis and promoted fibrosis 
      resolution. However, the signal-transducing events that are activated by ER 
      stress after HSCs activation were incompletely understood. In this study, we 
      induced ER stress with thapsigargin (TG), and determined the activation of 
      calpain and the cleavage of caspase by analyzing the protein levels and the 
      correspondingly increased intracellular calcium levels and the induction of the 
      proapoptotic transcription factor CHOP. Moreover, the phosphorylation of JNK and 
      p38 MAPK were followed by the activation of the executioner caspases, caspase-3. 
      As expected, preventing an increase in intracellular calcium levels using 
      intracellular calcium chelators, EGTA, and BAPTA/AM, could substantially inhibit 
      the phosphorylation of JNK and p38 MAPK, abolish the activation of calpains, 
      namely caspase-12, caspase-9, and caspase-3, and provide significant protection 
      for TG-treated activated HSCs. Interestingly, pretreatment with p38 MAPK 
      inhibitor SB202190, JNK inhibitor SP600125, the pan-caspase inhibitor z-VAD-FMK, 
      or calpain inhibitors calpeptin, significantly reduced the cell apoptosis and the 
      cleavage of caspase-12 and caspase-3. However, pretreatment with z-VAD-FMK failed 
      to reduce the activation of calpain. Additionally, pretreatment with SB202190 and 
      SP600125 also decreased the expression of CHOP. Importantly, PDGF-induced 
      collagen Col1alpha1 and alpha-smooth muscle actin (alpha-SMA), markers for the perpetuation 
      phase of HSCs activation, were inhibited in TG-treated activated HSCs. These 
      findings showed that the Calpain/Caspase-12 activation induced by ER stress and 
      the JNK/p38 MAPK phosphorylation induced by the increase of intracellular calcium 
      concentration releasing from ER are the novel signaling pathway underlying the 
      molecular mechanism of fibrosis recovery.
FAU - Huang, Yan
AU  - Huang Y
AD  - School of Pharmacy, Institute for Liver Diseases, Anhui key laboratory of 
      bioactivity of natural products, Anhui Medical University, Hefei, China, 
      aydhy@126.com.
FAU - Li, Xiaohui
AU  - Li X
FAU - Wang, Yarui
AU  - Wang Y
FAU - Wang, Huan
AU  - Wang H
FAU - Huang, Cheng
AU  - Huang C
FAU - Li, Jun
AU  - Li J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140625
PL  - Netherlands
TA  - Mol Cell Biochem
JT  - Molecular and cellular biochemistry
JID - 0364456
RN  - 0 (Actins)
RN  - 0 (Calcium Chelating Agents)
RN  - 0 (Caspase Inhibitors)
RN  - 0 (Collagen Type I)
RN  - 0 (Collagen Type I, alpha 1 Chain)
RN  - 0 (Ddit3 protein, rat)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (smooth muscle actin, rat)
RN  - 147336-12-7 (Transcription Factor CHOP)
RN  - 67526-95-8 (Thapsigargin)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 3.4.22.- (Calpain)
RN  - EC 3.4.22.- (Casp12 protein, rat)
RN  - EC 3.4.22.- (Caspase 12)
SB  - IM
MH  - Actins/metabolism
MH  - Animals
MH  - *Apoptosis/drug effects
MH  - Calcium Chelating Agents/pharmacology
MH  - *Calcium Signaling/drug effects
MH  - Calpain/*metabolism
MH  - Caspase 12/*metabolism
MH  - Caspase Inhibitors/pharmacology
MH  - Cell Line
MH  - Collagen Type I/metabolism
MH  - Collagen Type I, alpha 1 Chain
MH  - Endoplasmic Reticulum/drug effects/*enzymology/pathology
MH  - *Endoplasmic Reticulum Stress/drug effects
MH  - Hepatic Stellate Cells/drug effects/*enzymology/pathology
MH  - JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors/*metabolism
MH  - Liver Cirrhosis/drug therapy/*enzymology/genetics/pathology
MH  - Protein Kinase Inhibitors/pharmacology
MH  - RNA Interference
MH  - Rats
MH  - Thapsigargin/pharmacology
MH  - Transcription Factor CHOP/genetics/metabolism
MH  - Transfection
MH  - p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors/*metabolism
EDAT- 2014/06/26 06:00
MHDA- 2015/10/27 06:00
CRDT- 2014/06/26 06:00
PHST- 2013/12/31 00:00 [received]
PHST- 2014/04/18 00:00 [accepted]
PHST- 2014/06/26 06:00 [entrez]
PHST- 2014/06/26 06:00 [pubmed]
PHST- 2015/10/27 06:00 [medline]
AID - 10.1007/s11010-014-2073-8 [doi]
PST - ppublish
SO  - Mol Cell Biochem. 2014 Sep;394(1-2):1-12. doi: 10.1007/s11010-014-2073-8. Epub 
      2014 Jun 25.