Tavares, A.M.V. / Article 1
46
oxidative stress index, GSH/GSSG ratio, was
decreased.
This apparent balance of various
redox state contributors present in a
decompensated cardiac scenario was also
evident in functional readouts, where cardiac
flow assessment, E/A ratio and ET were
depressed in the AMI group, while TF and
MDDT did not change. Moreover, MPI was
found to be markedly increased and was
significantly negatively correlated with EF.
The clear reduction of LVFS characterizes an
impairment of ventricular contractility
associated with an expressive LV chamber
enlargement, as can be seen by the
enhanced systolic diameter.
Although diastolic diameter was not
changed, an evident loss of systolic function
was witnessed. Additionally, it was observed
that although the LV rapid filling was normal,
the slow filling was depressed and the EV
was minor, showing that diastolic function was
also depressed in the AMI group at this time
point. A strong correlation between diastolic
dysfunction (higher E/A ratio) and oxidative
stress was also demonstrated (Figure 4A).
It has previously been shown that
ROS generated in the immediate post-AMI
period can also function to modulate cardiac
inotropism, inducing cardiac hypertrophy and
apoptosis. These events reduce calcium
myofilament sensitivity and cardiac
contractility, contributing to the development
of heart failure [6].
While we did not find increased
myocardial oxidative damage, as observed by
protein oxidation and lipid peroxidation data,
we did observe diminished antioxidant
defenses through decreased GPx activity at
48 hours post-MI. GPx is an important
enzyme that catalyzes the reduction of H
2
O
2
and hydroperoxides, preventing the formation
of other more toxic radicals, such as
.
OH [38].
Furthermore, we found a positive
correlation between GPx and EF, suggesting
a strong association between cardiac function
and the activity of this enzyme. These data
corroborate previous findings which
demonstrated that GPx overexpression
inhibits the development of LV remodeling
and failure after AMI, which could contribute
to the improved survival [38], attenuation of
diastolic dysfunction, myocyte hypertrophy,
and interstitial fibrosis in diabetes [39].
We also analyzed myocardial CAT
activity and protein expression, but found no
significant differences between groups.
Studies suggest that CAT activity and
expression have minor relevance to GPx in
cardiac tissue [11]. We also did not note
important differences in myocardial SOD
activity or protein expression between groups,
leading us to believe that O
2
.-
concentration is
not significantly altered in our model.
Tissue production of O
2
.-
and,
consequently, low levels of H
2
O
2
, are
maintained by the basal activity of endothelial
NADPH oxidases and by mitochondrial
electron chain leakage, and is necessary for
endothelial growth and proliferation [40].
Under pathological conditions such as AMI,
agonist-induced activation of NADPH oxidase
and the subsequent activation of xanthine
oxidase, as well as the uncoupling of eNOS,
result in the production of large quantities of
H
2
O
2
, leading to cardiac dysfunction. For
instance, when H
2
O
2
diffuses to adjacent
muscle tissue, it can induce hypertrophy [41].
Interestingly, myocardial concentration
of H
2
O
2
was diminished at 48 hours post-AMI
in our study. We believe that this finding
suggests countervailing survival mechanisms
acting against H
2
O
2
in order to maintain
cardiac function in this temporal window
following MI. Among these mechanisms are
novel antioxidant proteins designated as
peroxiredoxins (Prxs). Among six known
mammalian Prxs, Prx-1,-2, -3, and -4 require
the small redox protein thioredoxin (Trx) as an
electron donor to remove H
2
O
2
. Prx-3 is