Oxidized phospholipids induce expression of human heme oxygenase-1 involving activation of cAMP-responsive element-binding protein

Heme oxygenase- 1 ( HO- 1) catalyzes the rate- limiting step in heme degradation, protects against oxidative stress, and shows potent anti- inflammatory effects. Oxidized phospholipids, which are generated during inflammation and apoptosis, modulate the inflammatory response by inducing the expression of several genes including HO- 1. Here we investigated the signaling pathways and transcriptional events involved in the induction of HO- 1 gene expression by oxidized 1- palmitoyl-2- arachidonoyl- sn- glycero- 3- phosphorylcholine ( OxPAPC) in human umbilical vein endothelial cells. OxPAPC up- regulated HO- 1 mRNA and protein in a time- and concentration- dependent manner, whereas pro- inflammatory agents like TNF-alpha and lipopolysaccharide did not significantly induce HO- 1 expression in human umbilical vein endothelial cells. Signaling pathways involved in the OxPAPC- mediated HO- 1 induction included protein kinases A and C, as well as the mitogen-activated protein kinases p38 and ERK. The cAMP-responsive element- binding protein ( CREB) was phosphorylated via these pathways in response to OxPAPC treatment and expression of a dominant- negative mutant of CREB inhibited OxPAPC- induced activity of a human heme oxygenase- 1 promoter- driven luciferase reporter construct. We identified a cAMP- responsive element and a Maf recognition element to be involved in the transcriptional activation of the HO- 1 promoter by OxPAPC. In gel shift assays we observed binding of CREB to the cAMP- responsive element after OxPAPC treatment. Induction of HO- 1 expression by lipid oxidation products via CREB may represent a feedback mechanism to limit inflammation and associated tissue damage.