Zhang Hongqiao, Forman Henry Jay
School of Natural Sciences, University of California, Merced, P.O. Box 2039, Merced, CA 95340, USA.
Am J Respir Cell Mol Biol. 2008 Apr;38(4):483-90. doi: 10.1165/rcmb.2007-0260OC. Epub 2007 Nov 29.
Heme oxygenase-1 (HO-1) catalyzes the rate limiting reaction of heme metabolism and plays critical roles in resistance to oxidative stress and other cellular functions. It is well known that HO-1 is induced in response to various stresses; however, the signaling pathways involved remain incompletely elucidated. Acrolein is an alpha,beta-unsaturated aldehyde present in cigarette smoke and also a product of lipid peroxidation. In this investigation we studied HO-1 induction in response to acrolein and determined the signaling pathways involved in human bronchial epithelial cells (HBE1 cells). We demonstrated that acrolein significantly increased the HO-1 mRNA content and promoter activity. Acrolein-mediated HO-1 induction was significantly attenuated by pan-protein kinase C (PKC) inhibitors RO318220, staurosporine, and PKC-delta selective inhibitor rottlerin and PKC-delta small interfering RNA. The HO-1 induction was also decreased by phosphatidylinositol 3-kinase (PI3K) inhibitors LY294002 and wortmannin. No significant effects on HO-1 induction were observed with the pretreatment of mitogen-activated protein kinase pathway inhibitors PD98059 (ERK), SB203580 (p38MAPK) and JNKi, and conventional and atypical PKC inhibitors. Furthermore, Nrf2 silencing significantly attenuated the HO-1 induction by acrolein. Inhibition of PKC-delta significantly decreased acrolein-mediated Nrf2 nuclear translocation, though inhibition of PI3K had no effect. Taken together, our results indicate that acrolein up-regulates HO-1 expression through both PKC-delta and PI3K pathways in HBE1 cells; PKC-delta appears to regulate HO-1 induction via modulating Nrf2 nuclear translocation, while PI3K may work through targeting on downstream signaling molecules other than Nrf2.
血红素加氧酶-1（HO-1）催化血红素代谢的限速反应，并在抵抗氧化应激和其他细胞功能中发挥关键作用。众所周知，HO-1是在各种应激反应中被诱导产生的；然而，所涉及的信号通路仍未完全阐明。丙烯醛是香烟烟雾中存在的一种α，β-不饱和醛，也是脂质过氧化的产物。在本研究中，我们研究了丙烯醛诱导的HO-1表达，并确定了人支气管上皮细胞（HBE1细胞）中所涉及的信号通路。我们证明，丙烯醛显著增加了HO-1 mRNA含量和启动子活性。泛蛋白激酶C（PKC）抑制剂RO318220、星形孢菌素以及PKC-δ选择性抑制剂rottlerin和PKC-δ小干扰RNA显著减弱了丙烯醛介导的HO-1诱导。磷脂酰肌醇3-激酶（PI3K）抑制剂LY294002和渥曼青霉素也降低了HO-1诱导。用丝裂原活化蛋白激酶途径抑制剂PD98059（ERK）、SB203580（p38MAPK）和JNKi以及传统和非典型PKC抑制剂预处理对HO-1诱导没有显著影响。此外，Nrf2沉默显著减弱了丙烯醛诱导的HO-1表达。抑制PKC-δ显著降低了丙烯醛介导的Nrf2核转位，而抑制PI3K则没有影响。综上所述，我们的结果表明，丙烯醛通过PKC-δ和PI3K途径上调HBE1细胞中HO-1的表达；PKC-δ似乎通过调节Nrf2核转位来调节HO-1诱导，而PI3K可能通过靶向Nrf2以外的下游信号分子发挥作用。
