The role of DNA damage in the pathogenesis of nitrate tolerance - nitrosative versus oxidative DNA damage
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Abstract
6.
Summary
Despite the lack of direct evidence from large clinical trials for mutagenic and
genotoxic effects of GTN therapy, the present study show s the
induction of pre-mutagenic lesions, such as 8-
oxo
-
G and O
6
-
me
-
G by GTN
t
reatment as well as
increased
formation of
DNA strand breaks.
These results
were obtained in
an
in vitro
(EA.hy 926
–
human endothelial cell line) and
in vivo
(Wistar rats and
C57BL/6
mice)
setting.
However, GTN
-
induced DNA damage had no effect on the degr
ee of nitrate
tolerance but only on other pathological side effects such as oxidative stress, as
confirmed by studies in MGMT knockout mice. Of clinical importance
, this study
establishes
potent
apoptotic properties of organic nitrates, which has been
demo
nstrated
by
the levels
of the novel apoptotic marker
and caspase
-
3 substrate,
fractin,
as well as levels of
cleaved caspase
-
3
, the activated form of this pro
-
apoptotic enzyme
.
The p
rotein
analy
tical data
ha
ve
been confirmed
by
an
independent
assay for
the
apoptosis
,
Cell death detection assay
(TUNEL)
.
First,
these GTN
-
mediated apoptotic effects may account for the previously reported anti
-
cancer effects of GTN therapy (probably based on induction of apoptosis in tumor
cells). Second, these GTN
-
mediated apop
totic effects may account for the
increased
mortality rates observed in the group of organic nitrate
-
treated patients as reported
by two independent meta
-
analysis
(probably due to induction of apoptosis in highly
beneficial endothelial progenitor cells as
well as in cardiomyocytes during wound
healing and cardiac remodeling)
.
Summary of the current investigations can be seen
in Figure 18.