Regulation of Endothleial Cell Apoptosis by HO-1 and CO

Beth Israel Deaconess Medical Center, Boston MA

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Abstract

DESCRIPTION(Applicant's abstract): 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.