Heme-oxygenase regulation by oxidized phospholipids

Evidence is accumulating that biologically active oxidized lipids present at sites of inflammation, in atherogenic lipoproteins, atherosclerotic lesions, and in membrane vesicles released from activated cells, play an essential role in various settings of chronic inflammation. These oxidized lipids stimulate endothelial cells to specifically bind monocytes typical for chronic inflammation, whereas other known inflammatory mediators (tumor necrosis factor, TNF; interleukin-1, IL-1; lipopolysaccharide, LPS) induce monocyte- as well as neutrophil adhesion, typical for acute inflammatory responses. Furthermore, oxidized phospholipids stimulate the expression of inflammatory genes (TF, MCP-1, IL-8) in endothelial cells, but also of heme-oxygenase-1 (HO-1), an enzyme that exerts potent anti- inflammatory activities. Activation of HO-1 was shown to interfere with leukocyte adhesion to the endothelium and to play a role in a variety of protective mechanisms. We plan to investigate the mechanisms of this unique activation of endothelial cells by oxidized phospholipids influencing inflammatory gene expression and cell adhesion in the vascular wall. Although HO-1 has been shown to be a major protective enzyme in the vascular wall, which is highly up-regulated during the development of the atherosclerotic lesion and which is induced by oxPAPC, the mechanism of HO-1 up-regulation is not known. Since MM-LDL/oxPAPC are both major factors in the pathogenesis of atherosclerosis and given the importance of HO-1 in the progression of chronic inflammation, the mechanism of HO-1 induction by lipid oxidation products is of fundamental importance. Therefore we want to investigate the signaling cascades and transcription events involved in the oxPAPC-mediated HO-1 induction. Identification of signaling pathways, transcription factors and promoter elements will eventually lead to the discovery of new drug targets in the treatment of chronic inflammation and atherosclerosis.

Biologically active oxidized phospholipids play an important role in chronic inflammatory diseases, including atherosclerosis. Oxidized lipids activate endothelial cells to bind monocytes, an initiating process in atherogenesis. Moreover, these lipids induce in endothelial cells the expression of pro-inflammatory genes, including tissue factor and chemokines, but also anti-inflammatory genes such as heme-oxygenase-1. It was shown that activation of heme-oxygenase-1 interferes with leukocyte-endothelial interaction and thus plays an important role in vascular homeostasis. Although it was shown that hemeoxygenase is an important vasculo-protective gene, little is known about its regulation. Our studies an signaling pathways and transcriptional regulation of heme-oxygenase showed that oxidized phospholipids regulate this gene via a new mechanism. Analysis of the promoter demonstrated that nuclear receptors, which are activated by drugs commonly used in the treatment of diabetes and lipid disorders, are involved in uopregulation of hemeoxygenase-1, and thus exert additional protective effects. These results should ultimately lead to identification of novel drug targets for the treatment of inflammatory diseases such as atherosclerosis.