New insights into signaling pathways of salicylate and metalloporphyrins

Aim of the study: I. Salicylate and heme oxygenase-1: The adhesion
molecule P-selectin has been shown to be a major determinant of
inflammatory responses. Different pharmacological agents including
salicylate have been shown to inhibit IL-4-induced P-selectin
expression in endothelial cells. Mechanisms responsible for
P-selectin inhibition, however, are as yet not very well known. In
the present work we confirmed this finding and aimed to elucidate
the events leading to this inhibition. II. Metalloporphyrins and
caspases: Apart from the beneficial effects of HO-1 on inflammatory
processes, HO-1 is known to provoke anti-apoptotic effects.
Metalloporphyrins are heme-analogous and are thus able to inhibit
the activity of the heme-converting enzyme HO-1. Therefore, they
are widely used and accepted tools in research investigating
functional aspects of HO-1. In studies concerning the
anti-apoptotic features of HO-1, different metalloporphyrins are
often employed to either stimulate HO-1-expression or inhibit its
activity. Apoptotic cell death is then quantified with various
assay methods, such as the measurement of caspase-3-like activity.
In an approach to determine potential anti-apoptotic features of
ASA-induced HO-1 we observed contradictory results in a respective
experimental setting. This led to the hypothesis that
metalloporphyrins exert actions other than their well-known
HO-1-dependent effects. Therefore, the second part of this work
deals with the specificity of metalloporphyrins. Aim of the study
was to find the cause for these contradictory results and further
investigate a potential effect of the metalloporphyrins on caspase
activity.