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p38‐MAPK‐ and caspase‐3‐mediated superoxide‐induced apoptosis of rat hepatic stellate cells: Reversal by retinoic acid
Author(s) -
Jameel Noor Mohamed,
Thirunavukkarasu Chinnasamy,
Wu Tong,
Watkins Simon C.,
Friedman Scott L.,
Gandhi Chandrashekhar R.
Publication year - 2009
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.21581
Subject(s) - superoxide , superoxide dismutase , oxidative stress , reactive oxygen species , glutathione peroxidase , catalase , apoptosis , chemistry , glutathione , hepatic stellate cell , p38 mitogen activated protein kinases , microbiology and biotechnology , biology , biochemistry , mapk/erk pathway , endocrinology , signal transduction , enzyme
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. J. Cell. Physiol. 218: 157–166, 2009. © 2008 Wiley‐Liss, Inc.