PI3K and ERK/Nrf2 pathways are involved in oleanolic acid-induced heme oxygenase-1 expression in rat vascular smooth muscle cells†

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.