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Acrolein Induces Heme Oxygenase-1 through PKC- and PI3K in Human Bronchial Epithelial Cells

¹ School of Natural Science, University of California at Merced, Merced, California

Correspondence and requests for reprints should be addressed to Henry Jay Forman, School of Natural Sciences, University of California, Merced, P.O. Box 2039, Merced, CA 95340. E-mail: hjforman{at}gmail.com

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 ,β-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- selective inhibitor rottlerin and PKC- 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- 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- and PI3K pathways in HBE1 cells; PKC- appears to regulate HO-1 induction via modulating Nrf2 nuclear translocation, while PI3K may work through targeting on downstream signaling molecules other than Nrf2.

Key Words: acrolein • heme oxygenase 1 • PKC- • Akt

CLINICAL RELEVANCE Heme oxygenase-1 (HO-1) induction is crucial in oxidative resistance. Understanding signaling for HO-1 induction by acrolein, a common toxicant, will help develop new strategies for the prevention of diseases associated with oxidative stress.