p38-MAPK- and caspase-3-mediated superoxide-induced apoptosis of rat hepatic stellate cells: reversal by retinoic acid.
Reactive oxygen species (ROS) activate retinoid-containing quiescent hepatic stellate cells (qHSCs) to retinoid-deficient fibrogenic myofibroblast-like cells (aHSCs). However, ROS also cause apoptosis of aHSCs, and apoptotic aHSCs are observed in inflammatory fibrotic liver. Here, we investigated mechanisms of the effects of oxidative stress on the survival of qHSCs and aHSCs. HSCs from normal rat liver were used after overnight culture (qHSCs), or in 3-5 passages (aHSCs). For in vivo induction of oxidative stress, tert-butylhydroperoxide was injected into control and CCl4-induced cirrhotic rats. Spontaneous caspase-3 activation and apoptosis, observed in cultured qHSCs, decreased with time and were unaffected by superoxide. In contrast, superoxide caused caspase-3 and p38-MAPK activation, reduction in Bcl-xL expression, and apoptosis in aHSCs. Inhibition of caspase-3 and p38-MAPK did not affect the viability of qHSCs in the absence or presence of superoxide, but inhibited superoxide-induced death of aHSCs. Glutathione (GSH) level and activities of superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) were lower in aHSCs than qHSCs. Superoxide increased GSH content, and activities of SOD, catalase and GPx in qHSCs but not in aHSCs. Incubation of 13-cis-retinoic acid (RA)-treated aHSCs with superoxide increased their GSH content significantly, and prevented superoxide-induced p38-MAPK and caspase-3 activation while dramatically reducing the extent of apoptosis. Finally, oxidative stress induced in vivo caused apoptosis of aHSCs in cirrhotic but not of qHSCs in control rats. These results suggest that the absence of retinoids render aHSCs susceptible to superoxide-induced apoptosis via caspase-3 and p38-MAPK activation.
Jameel
Noor Mohamed
NM
Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.
Thirunavukkarasu
Chinnasamy
C
Wu
Tong
T
Watkins
Simon C
SC
Friedman
Scott L
SL
Gandhi
Chandrashekhar R
CR
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D053148:Caspase 3 / Q000378:metabolism*; D002374:Catalase / Q000378:metabolism; D004789:Enzyme Activation; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology; D008297:Male; D018384:Oxidative Stress; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D016192:Resting Phase, Cell Cycle; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D017382:Reactive Oxygen Species; D013481:Superoxides; D014212:Tretinoin; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D048051:p38 Mitogen-Activated Protein Kinases; C505410:Casp3 protein, rat; D053148:Caspase 3; D005978:Glutathione
Br J Pharmacol. 2003 Jun;139(4):765-74
12813000
Liver. 1998 Feb;18(1):39-48
9548266
J Clin Invest. 1995 Nov;96(5):2461-8
7593635
J Clin Invest. 1998 Aug 1;102(3):538-49
9691091
J Pharmacol Exp Ther. 2002 Nov;303(2):468-75
12388625
Agents Actions. 1991 Nov;34(3-4):339-44
1667243
J Hepatol. 2003 Jul;39(1):38-46
12821042
Gut. 2006 Jan;55(1):90-7
16041064
Biochem Biophys Res Commun. 1993 Aug 16;194(3):1044-50
8352762
FASEB J. 1999 Jan;13(1):155-68
9872940
Hepatology. 1997 Aug;26(2):351-7
9252145
Biochim Biophys Acta. 2007 Jan;1772(1):66-71
17011172
Hepatology. 1997 Feb;25(2):361-7
9021948
Arch Toxicol. 2005 Feb;79(2):102-9
15645217
J Hepatol. 2004 Oct;41(4):567-75
15464236
J Biol Chem. 2001 Oct 12;276(41):38152-8
11477100
Circulation. 1997 Nov 18;96(10):3602-9
9396461
Hepatology. 2005 May;41(5):1074-84
15841469
Mutat Res. 2000 Mar 3;466(1):9-15
10751720
Semin Liver Dis. 1996 Feb;16(1):13-30
8723320
J Hepatol. 1992 Mar;14(2-3):211-20
1500685
J Hepatol. 2004 Sep;41(3):370-6
15336438
Physiol Rev. 2001 Apr;81(2):807-69
11274345
Gut. 2004 Jul;53(7):1010-9
15194653
Mutat Res. 1995 Feb;339(1):37-59
7877644
Hepatology. 1997 Oct;26(4):913-21
9328313
J Cell Physiol. 2005 Aug;204(2):654-65
15828022
Free Radic Res. 1999 Oct;31(4):273-300
10517533
J Clin Invest. 1990 Dec;86(6):2062-70
2254460
Hepatology. 2006 Mar;43(3):454-63
16496303
Hepatology. 1998 Mar;27(3):720-6
9500700
Gastroenterology. 1998 Dec;115(6):1541-51
9834283
J Biol Chem. 2000 Jan 28;275(4):2247-50
10644669
Gut. 2006 Aug;55(8):1174-82
16423888
Hepatology. 2006 Nov;44(5):1267-77
17058265
Biochem Pharmacol. 2004 Mar 15;67(6):1025-33
15006539
Semin Liver Dis. 2001 Aug;21(3):311-35
11586463
Physiol Rev. 1994 Jan;74(1):139-62
8295932
Neurochem Int. 2000 Jan;36(1):1-5
10566953
FEBS Lett. 1999 Apr 9;448(2-3):206-10
10218477
Hepatology. 2004 Jan;39(1):97-108
14752828