During
myocardial reperfusion injury, oxidative stress induces DNA damage and activation of the nuclear
enzyme poly(ADP-ribose) polymerase-1 (PARP-1), resulting in cardiovascular dysfunction. In this study, we investigated the
biological effects and the molecular mechanisms of two structurally unrelated selective inhibitors of PARP-1,
3-aminobenzamide (3-AB) and
1,5-dihydroxyisoquinoline (-DIQ), in an in vivo model of
myocardial ischemia and reperfusion. Male Wistar rats were subjected to 30 min of occlusion followed by reperfusion (up to 24 h) of the left anterior descending coronary artery. In vehicle-treated rats,
ischemia and reperfusion induced extensive myocardial damage and marked neutrophil infiltration (as indicated by
myeloperoxidase activity).
Caspase 3 was maximally activated within 15 to 30 min after reperfusion, suggesting the occurrence of apoptosis. These inflammatory events were associated with activation of the
transcription factor activator protein-1 (AP-1) in the reperfused hearts. Treatment of the rats with the PARP-1 inhibitors, 3-AB or 1,5-DIQ, reduced myocardial damage, neutrophil infiltration, and
caspase activation. This cardioprotection was associated with reduction of
AP-1 activation. Furthermore, in in vitro
cytokine-stimulated human endothelial cells, expression of
intercellular adhesion molecule 1, vascular cellular adhesion molecule 1, and P- and
E-selectin was significantly reduced by treatment with 3-AB or 1,5-DIQ. On the contrary, in vivo or in vitro treatment with
nicotinic acid, a chemical analogue of
PARP inhibitors, which lacks the ability to inhibit the catalytic activity of PARP-1, was unable to afford any protective effect and to prevent activation of
AP-1. Our data demonstrate that inhibition of catalytic activity of PARP-1 may provide cardioprotection by regulating stress-induced signal transduction pathways.