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From the Department of Medicine,*
St. Michael's
Hospital and University of Toronto, Toronto, Ontario, Canada; the
Departments of Pathology
and
Medicine,
University Hospital, Uppsala,
Sweden; and the Transplantation Laboratory,§
University of Helsinki, Helsinki, Finland
Ischemia-induced tissue activation may contribute to the
pathogenesis of graft vasculopathy, but the mediators
implicated have only partially been characterized. To gain further
insight into the molecular mechanisms involved, syngeneic rat
aortic transplants with cold-storage-induced vasculopathy were studied
for differentially expressed mRNA transcripts. Vessel segments were
exposed to either 1 or 18 hours of cold ischemia, followed by
transplantation into syngeneic recipients. After 3 days or 4
weeks, the grafts were removed and total mRNA was isolated and
used for differential display to identify modulation of transcript
expression related to prolonged storage. Using 15 sets of random
primers, 17 polymerase chain reaction products were
up-regulated and 2 were down-regulated in grafts exposed to 18 hours of
ischemia. Sequencing of these amplicons showed that 6 had a high degree
of homology to known sequences whereas 13 had no homology to any of the
genes in the database. Two of the differentially displayed amplicons
(capping protein and eotaxin) were cloned,
re-amplified, and used as probes for Northern blot analysis to
confirm their differential expression. Immunohistochemistry using
monoclonal antibodies against capping protein-
and eotaxin confirmed
that both proteins are expressed in the media of normal aortas and that
there was an increased expression in vessels exposed to prolonged
ischemia albeit that the increase at the protein level seemed less
compared with changes in transcript expression. Northern blots with RNA
from aortic allografts exposed to prolonged ischemic storage also
showed increased levels of capping protein and eotaxin mRNA whereas
there was a decrease in the relative amount of these transcripts in
vessels exposed to balloon denudation, suggesting that the
increase after prolonged ischemic exposure is not the result of a
nonspecific response to injury. Based on the biological characteristics
of capping protein and eotaxin it is conceivable that they play a
pathogenetic role in ischemia-induced vessel wall remodeling. It
remains to be established whether these genes or their products serve
as target molecules for therapeutic interventions to prevent or treat
cold-storage-induced graft vasculopathy.
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