Endothelial cell (EC) apoptosis, such as it occurs during acute or chronic inflammation, is a highly pro-inflammatory event that can lead to irreversible tissue injury, organ failure and disease. Understanding how EC protect themselves from undergoing apoptosis in situations of stress may be critical in the development of therapeutic strategies aimed suppress the deleterious effects associated with acute and/or chronic inflammation. One of the physiological mechanisms by which EC protect themselves from undergoing apoptosis relies on the expression of a series of cytoprotective genes. We will study one of such protective genes in this proposal, the stress responsive gene heme oxygenase-l (HO-1). Under inflammatory conditions HO-1 becomes the rate limiting enzyme in the catabolism of heme to yield equimolar amounts of bilirubin, free iron and the gaseous molecule carbon monoxide (CU). Our preliminary studies suggest that the cytoprotective effects of HO-1 are largely mediated through the generation of CO. Expression of HO-1 in vivo can suppress acute inflammatory reactions such as those associated with the rejection of a transplanted organ. Presumably, this cytoprotective effect relies on the ability of HO-1 to prevent EC apoptosis. This is supported by the observation that expression of HO-1 in vitro can prevent EC from undergoing apoptosis. In both cases the cytoprotective effect of HO-1 is mediated through the generation of CO. The anti-apoptotic effect of HO-1/CO is dependent on the activation of the p38 mitogen activated protein kinase (MAPK) signal transduction pathway and the activation of the transcription factor NF-KB. Presumably this events lead to the up-regulation of expression of NF-KB dependent protective genes that contribute to suppress EC apoptosis. This proposal aims to analyze the mechanism(s) by which HO-1 and its derivative CO protect EC from undergoing apoptosis. We propose to identify mechanism by which HO-1 and CO activate p38 MAPK as well as the transcription factor NF-KB and to determine how these events contribute to prevent EC apoptosis. We believe that the results gained in these application, which reveal for the first time the potent anti-apoptotic effect of CO, will provide valuable information that will contribute to the development of new approaches to overcome pathologic conditions associated with acute and/or chronic inflammation, including septic shock, atherosclerosis and/or the rejection of immediately vascularized transplanted organs.
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| Yamashita, Kenichiro; Ollinger, Robert; McDaid, James et al. (2006) Heme oxygenase-1 is essential for and promotes tolerance to transplanted organs. FASEB J 20:776-8 |
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| Camara, Niels Olsen Saraiva; Soares, Miguel Parreira (2005) Heme oxygenase-1 (HO-1), a protective gene that prevents chronic graft dysfunction. Free Radic Biol Med 38:426-35 |
| Ollinger, Robert; Bilban, Martin; Erat, Anna et al. (2005) Bilirubin: a natural inhibitor of vascular smooth muscle cell proliferation. Circulation 112:1030-9 |
| Wang, Hongjun; Lee, Soo Sun; Gao, Wenda et al. (2005) Donor treatment with carbon monoxide can yield islet allograft survival and tolerance. Diabetes 54:1400-6 |
| Soares, Miguel P; Seldon, Mark P; Gregoire, Isabel Pombo et al. (2004) Heme oxygenase-1 modulates the expression of adhesion molecules associated with endothelial cell activation. J Immunol 172:3553-63 |
| Wagener, Frank A D T G; Volk, Hans-Dieter; Willis, Dean et al. (2003) Different faces of the heme-heme oxygenase system in inflammation. Pharmacol Rev 55:551-71 |
| Otterbein, Leo E; Soares, Miguel P; Yamashita, Kenichiro et al. (2003) Heme oxygenase-1: unleashing the protective properties of heme. Trends Immunol 24:449-55 |
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