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PI3K and ERK/Nrf2 pathways are involved in oleanolic acid‐induced heme oxygenase‐1 expression in rat vascular smooth muscle cells
Author(s) -
Feng Jian,
Zhang Ping,
Chen Xuxin,
He Guoxiang
Publication year - 2011
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.23065
Subject(s) - wortmannin , mapk/erk pathway , heme oxygenase , vascular smooth muscle , ly294002 , pi3k/akt/mtor pathway , p38 mitogen activated protein kinases , protein kinase b , microbiology and biotechnology , chemistry , downregulation and upregulation , kinase , signal transduction , heme , biology , biochemistry , endocrinology , smooth muscle , gene , enzyme
Oleanolic acid (OA), a widely used plant‐derived triterpenoid, has been shown to possess potent antiatherosclerotic effects, which may be associated with the induction of heme oxygenase‐1 (HO‐1). However, the underlying mechanisms involved in the effect of OA on HO‐1 expression are unclear. In the current study, primary rat vascular smooth muscle cells (VSMCs) were exposed to OA and we found that it enhanced HO‐1 expression in a concentration‐ and time‐dependent manner, accompanied by increased HO‐1 activity. VSMCs treated with OA exhibited activation of Akt, p38 and extracellular‐signal‐regulated kinase (ERK). Wortmannin (a PI3K inhibitor) and PD98059 (an ERK inhibitor) attenuated OA‐induced HO‐1 expression, whereas SB203580 (a p38 inhibitor) had no effect. The transcription factor NF‐E2‐related factor 2 (Nrf2) is a key regulator of HO‐1 expression. OA treatment increased Nrf2 nuclear translocation, which was also inhibited by wortmannin and PD98059. Furthermore, transfection of VSMCs with the Nrf2 siRNA‐expressing lentiviral vector decreased HO‐1 expression induced by OA. Finally, pretreatment of VSMCs with OA remarkably reduced hydrogen peroxide‐induced cell apoptotic death, and this effect was greatly attenuated in the presence of ZnPP (a HO‐1 inhibitor), wortmannin or PD98059. Taken together, these results suggest that activation of Akt and ERK is required for OA‐induced activation of Nrf2 followed by upregulation of HO‐1 expression in VSMCs, which may confer an adaptive survival response in atherosclerosis. J. Cell. Biochem. 112: 1524–1531, 2011. © 2011 Wiley‐Liss, Inc.