Aims: 

Chronic hypertension can induce cell death (apoptosis) and fibrotic remodeling in arterial wall via oxidative stress and consequent poly(ADP-ribose)polymerase enzyme (PARP) activation. In our previous work we have proved that PARP inhibition improves vasomotor function and decreases vascular remodeling caused by permanent high blood pressure. In our recent work we have investigated the effect of a PARP inhibitor (L-2286) on the activation state of signal transduction pathways in spontaneously hypertensive rats (SHR).

Methods: 

Male 10-weeks-old SHRs received 5 mg/kg/day L-2286 orally for 32 weeks (SHR-L). As positive control, placebo-treated SHRs were used (SHR-C). Male Wistar rats belonged to the negative control group. At the end of the experimental period to detect the oxidative damage 3-nitrotyrosine formation was measured in histologic samples from carotid arteries and aortas. PARP activation was determined by immunohystochemistry. The activation state of signal transduction proteins (Akt-1 and MAP-kinases) in the vessels were monitored by Western blotting. Furthermore caspase-independent cell death provoking apoptosis inducing factor (AIF) translocation was also studied.

Results: 

L-2286 treatment decreased significantly (p<0.05) the expression of nitrotyrosine and PARP activation in SHR-L. In addition PARP inhibition enhanced the phosphorylation of the prosurvival factor Akt-1 (p<0.05) while phosphorylation of ERK, JNK and p-38 MAPK were significantly (p<0.05) decreased in SHR-L group. In SHR-C group upregulated translocation of AIF was demonstrated which was decreased in SHR-L animals due to L-2286 treatment.

Conclusion: 

We demonstrated that in the background of its vasoprotective effect PARP inhibition decreases oxidative stress and apoptosis via modulation of Akt and MAPKs signaling pathways.