This work characterizes the protective effects of ANP preconditioning in ischemia-reperfusion
injury of the isolated perfused rat liver. It was of particular interest to evaluate
the influence of ANP on the mode of cell death occurring during cold ischemia and
reperfusion and to elucidate the involved signal transduction pathways.
Apoptotic cell death was mainly seen after cold liver storage, whereas necrosis was
predominant in the reperfusion period.
It could be demonstrated for the first time that preconditioning with ANP was able to
reduce both apoptotic as well as necrotic cell death. After cold ischemia, in particular
hepatocytes were protected against apoptosis. After reperfusion, protection against
necrosis comprised hepatocytes and sinusendothelial cells predominantly in the periportal
liver areas.
As target molecules for ANP action, the cGMP-dependent protein kinases did not seem to
be responsible for the conferred cytoprotection. In the liver, no expression of these
kinases could be detected and a functional connection could not be derived. In contrast,
the cAMP-dependent protein kinases were identified to promote survival. This was further
supported by the ability of ANP to directly activate cAMP-dependent protein kinases in
livers and hepatocytes.
An early transcriptional induction of HO-1 by ANP independent of cGMP could be
demonstrated. The induction of heme oxygenase-1 by ANP might not be responsible for
the observed hepatoprotection, since inhibition of HO-1 activity did not abrogate the ANP
effect. Interestingly, cell-type specific evaluation detected that induction of HO-1 in livers
by ANP is exclusively restricted to Kupffer cells.
In summary, this thesis gives new insights into the actions of the cardiovascular hormone
ANP in IRI of the rat liver. This data helps to understand the mechanisms of how ANP
mediates cytoprotection by illuminating effects and potential pathways, an important
prerequisite for a rational application in therapy.
This work was supported by the Deutsche Forschungsgemeinschaft (DFG: Ge 576/14-2
and FOR 440/1, TP2)