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Vol. 59, Issue 6, 1497-1505, June 2001
Departments of Biochemistry (R.H., Z.B., B.S.) and Medical
Chemistry (E.O.) and 1st Department of Medicine (K.T.), University of
Pécs, Faculty of Medicine, Pécs, Hungary; and N-Gene
Research Laboratories, Inc., Budapest, Hungary (P.L.-N.)
Ischemia-reperfusion induces reactive oxygen species (ROS) formation,
and ROS lead to cardiac dysfunction, in part, via the activation of the
nuclear poly(ADP-ribose) polymerase (PARP, called also PARS and
ADP-RT). ROS and peroxynitrite induce single-strand DNA break formation
and PARP activation, resulting in NAD+ and ATP depletion,
which can lead to cell death. Although protection of cardiac muscle by
PARP inhibitors can be explained by their attenuating effect on
NAD+ and ATP depletion, there are data indicating that PARP
inhibitors also protect mitochondria from oxidant-induced injury.
Studying cardiac energy metabolism in Langendorff heart perfusion
system by 31P NMR, we found that PARP inhibitors
(3-aminobenzamide, nicotinamide, BGP-15, and 4-hydroxyquinazoline)
improved the recovery of high-energy phosphates (ATP, creatine
phosphate) and accelerated the reutilization of inorganic phosphate
formed during the ischemic period, showing that PARP inhibitors
facilitate the faster and more complete recovery of the energy
production. Furthermore, PARP inhibitors significantly decrease the
ischemia-reperfusion-induced increase of lipid peroxidation, protein
oxidation, single-strand DNA breaks, and the inactivation of
respiratory complexes, which indicate a decreased mitochondrial ROS
production in the reperfusion period. Surprisingly, PARP inhibitors, but not the chemically similar 3-aminobenzoic acid, prevented the
H2O2-induced inactivation of cytochrome oxidase
in isolated heart mitochondria, suggesting the presence of an
additional mitochondrial target for PARP inhibitors. Therefore, PARP
inhibitors, in addition to their important primary effect of decreasing
the activity of nuclear PARP and decreasing NAD+ and ATP
consumption, reduce ischemia-reperfusion-induced endogenous ROS
production and protect the respiratory complexes from ROS induced
inactivation, providing an additional mechanism by which they can
protect heart from oxidative damages.
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