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Weber, Nina Claudia (2002): Influence of the Atrial Natriuretic Peptide on TNF- αα α -activated human endothelial cells: Regulation of adhesion molecule expression and cytoskeleton changes. Dissertation, LMU München: Faculty of Chemistry and Pharmacy
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Abstract

The present work deals with the inhibitory action of ANP on TNF- -induced expression of adhesion molecules (ICAM-1, VCAM-1, E-selectin), chemokines (MCP-1), and cytoskeleton changes in human endothelial cells. 5.1.1 Effect of ANP on TNF- α αα-induced CAM expression The following diagram shows a schematic outdraw of the summerized results of the first part of the present work. figure 1 summary: schematic diagram of the signal transduction pathways clarified by the first section of the present work It has been shown before that TNF- increases the expression of cell adhesion molecules E-selectin and ICAM-1 via activation of the transcription factor NF- B. We could show that ANP is able to inhibit the activation of NF- B via binding its guanylyl-cyclase-coupled NPR-A and -B receptor. We could further elucidate the molecular mechanism leading to the inhibition of NF- B activation by ANP. ANP was shown to transcriptionally activate the expression of I B isoforms. In consequence of the ANP mediated inhibition of NF- B DNA-binding activity we could demonstrate an attenuated surface expression of E-selectin and ICAM-1. E-selectin ICAM-1 NF- κκB κ B 5.1.2 Effect of ANP on TNF- αα α -induced cytoskeleton and perme- ability changes The following figure shows an outdraw of the summerized results of the second part of the present work. figure 2 summary: schematic diagram of the signal transduction pathways clarified by the second section of the present work TNF- has been shown to induce changes in cytoskeleton and macromolecule permeability of endothelial cells. We have shown here for the first time that ANP is able to abrogate both TNF- - induced effects via its guanylyl-cyclase-coupled NPR-A receptor. Moreover, ANP was shown to reduce TNF- -induced F-actin polymerization and stress fiber formation via the inhibition of p38 MAPK and its downstream target HSP27. Furthermore we could report here for the first time a decrease in TNF- -induced macromolecule permeability by ANP. The deactivation of p38 MAPK was demonstrated to be mediated via a significant transcriptional induction of the MKP-1 by ANP. intercellular gap5.1.3 Effect of ANP on TNF- α αα-induced MCP-1 expression The results of the third part of the present work are summerized in figure 3. figure 3 summary: schematic diagram of the signal transduction pathways clarified by the first and third section of the present work It is known that TNF- induces the release of MCP-1 during inflammatory processes via influencing the transcription factor NF- B and the p38 MAPK pathway. We could report here for the first time a decreased TNF- -induced MCP-1 expression by treatment of endothelial cells with ANP. The observed ANP effect was shown to be mediated via the particulate guanylyl-cyclase-coupled NPR. Furthermore we show that trancriptional induction of MKP-1 by ANP is essential for inhibition of TNF- - induced MCP-1 expression by ANP. In summary the data presented here provides evidence that ANP is able to preserve the structure and function of endothelial cells. These observations are of special importance because there is clear evidence that endothelial cell dysfunction is the cause for many acute and chronic vascular diseases (Biegelsen and Loscalzo 1999). The potency of an endogenous compound, i.e. ANP, to protect against such endothelial dysfunction points to an antiinflammatory and antiatherogenic potential of this cardiovascular hormone. This work has been supported by the DFG (Vo376/8-1). macromolecule