Prevention of Ischemia-Reperfusion Injury in the Rat Liver by Atrial Natriuretic Peptide

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).