Atrial Natriuretic Peptide - a regulatory protein in endothelial activation. Characterization of its in vivo anti-inflammatory action and the molecular targets involved

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The endogenous cardiovascular peptides ANP (INN: carperitide, HANP®) and BNP (INN: nesiritide, Natrecor®) are novel drugs for the treatment of acute heart failure. A substantial amount of in vitro work indicates that ANP affects important signalling pathways involved in endothelial cell activation and inflammation. This proposal aims to investigate the in vivo relevance of ANP as a regulator protein in endothelial cell activation. Thereby, both the role of exogenously administered, as well as endogenously produced ANP will be of interest. Consequently, the first part of the work will focus on the effect of ANP on endothelial activation as well as the influence of ANP on leukocyte-endothelium interactions in mice treated with lipopolysaccharide (LPS). Special attention will be given to the responsible signalling cascades and major target molecules such as the phosphatase MKP-1. In the second part of the project, the role of the endogenous ANP/NPR/cGMP-system will be characterized in LPS-induced inflammation by use of respective transgenic animals. In summary the proposed work aims to find out whether ANP is a regulatory protein in endothelial cell activation and inflammation in vivo and attempts to elucidate the underlying molecular mechanisms.