PI3K and ERK/Nrf2 Pathways Are Involved in Oleanolic Acid-Induced Heme Oxygenase-1 Expression in Rat Vascular Smooth Muscle Cells
PI3K and ERK/Nrf2 Pathways Are Involved in Oleanolic Acid-Induced Heme Oxygenase-1 Expression in Rat Vascular Smooth Muscle Cells
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DOI：
10.1002/jcb.23065
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发表时间：
2011-06-01
影响因子：
4
通讯作者：
He, Guoxiang
中科院分区：
文献类型：
--
作者：
Feng, Jian;Zhang, Ping;He, Guoxiang
油酸（OA）是一种广泛应用的植物源三萜类化合物，具有抗动脉粥样硬化作用，其作用机制可能与诱导血红素加氧酶-1（HO-1）有关。然而，OA对HO-1表达影响的潜在机制尚不清楚。在目前的研究中，原代大鼠血管平滑肌细胞（VSMCs）暴露于OA，我们发现，它增强HO-1的表达在浓度和时间依赖性的方式，伴随着增加HO-1活性。OA处理的VSMCs表现出Akt、p38和细胞外信号调节激酶（ERK）的激活。Wortmannin（PI 3 K抑制剂）和PD 98059（ERK抑制剂）减弱OA诱导的HO-1表达，而SB 203580（p38抑制剂）没有影响。转录因子NF-E2相关因子2（Nrf 2）是HO-1表达的关键调节因子。OA处理增加了Nrf 2核转位，这也被渥曼青霉素和PD 98059抑制。此外，用表达Nrf 2 siRNA的慢病毒载体转染VSMC可降低OA诱导的HO-1表达。最后，预处理的VSMCs与OA显着减少过氧化氢诱导的细胞凋亡死亡，这种效果大大减弱ZnPP（HO-1抑制剂），渥曼青霉素或PD 98059的存在下。综上所述，这些结果表明，Akt和ERK的激活是OA诱导的Nrf 2激活所必需的，随后是VSMC中HO-1表达的上调，这可能赋予动脉粥样硬化中的适应性生存反应。J.细胞。112：1524-1531，2011中。(C)2011 Wiley-Liss，Inc.
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. (C) 2011 Wiley-Liss, Inc.