Cardiovascular Research Advance Access [Accepted Manuscript] published online on May 14, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp144
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PARP inhibition delays transition of hypertensive cardiopathy to heart failure in spontaneously hypertensive rats
1 First Department of Medicine, Division of Cardiology, University of Pecs, Pecs, Hungary
2 Department of Biochemistry and Medical Chemistry, University of Pecs, Pecs, Hungary
3 Department of Pathology, University of Pecs, Pecs, Hungary
4 Department of Surgical Research and Techniques, University of Pecs, Pecs, Hungary
5 Department of Organic and Medicinal Chemistry, School of Medicine, University of Pecs, Pecs, Hungary
Corresponding author: Kalman Toth MD, ScD, FESC, First Department of Medicine, Division of Cardiology, School of Medicine, University of Pecs, Hungary, 13 Ifjusag St., H-7624 Pecs, Hungary, Tel.:+36-72/536-145, Fax.:+36-72/536-146, E-mail address: kalman.toth{at}aok.pte.hu
Aims: Oxidative stress followed by abnormal signaling can play a critical role in the development of long-term, high blood pressure-induced cardiac remodeling in heart failure (HF). Since oxidative stress-induced poly(ADP-ribose)polymerase (PARP) activation and cell death have been observed in several experimental models, we investigated the possibility that inhibition of nuclear PARP improves cardiac performance and delays transition from hypertensive cardiopathy to HF in a spontaneously hypertensive rat (SHR) model of HF.
Methods: SHRs were divided into two groups: one received no treatment (SHR-C) and the other (SHR-L) received 5 mg/kg/day L-2286 (PARP-inhibitor) orally for 46 weeks. A third group was a normotensive age-matched control group (CFY) and a fourth was a normotensive age-matched group receiving L-2286 treatment 5 mg/kg/day (CFY+L).
Results: At the beginning of the study systolic function was similar in both CFY and SHR groups. In the SHR-C group at the end of the study eccentric hypertrophy with poor left ventricular (LV) systolic function was observed, while PARP inhibitor treatment preserved systolic LV function. Due to these favourable changes, the survival rate of SHRs was significantly improved (p<0.01) by the administration of the PARP inhibitor (L-2286). The PARP inhibitor used did not affect the elevated blood pressure of SHR rats, but moderated the level of plasma-BNP (p<0.01) and favorably influenced all the measured gravimetric parameters (p<0.05) and the extent of myocardial fibrosis (p<0.05). The inhibition of PARP increased the phosporylation of Akt-1/GSK-3β (p<0.01), ERK 1/2 (p<0.01), and PKC 
(p<0.01), and decreased the phosphorylation of JNK (p<0.05), p-38 MAPK (p<0.01), PKC pan βII and PKC 
/
(p<0.01), PKC 
/βII and 
(p<0.05).
Conclusion(s): These data demonstrate that chronic inhibition of PARP induces long-term favorable changes in the most important signaling pathways related to oxidative stress. PARP inhibition also prevents remodeling, preserves systolic funtion and delays transition of hypertensive cardiopathy to HF in SHRs.
Time for primary review: 33 Days
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