Cardiovascular Research Advance Access originally published online on May 14, 2009
Cardiovascular Research 2009 83(3):501-510; 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, School of Medicine, University of Pecs, 13 Ifjusag St., H-7624 Pecs, Hungary
2 Department of Biochemistry and Medical Chemistry, School of Medicine, University of Pecs, Pecs, Hungary
3 Department of Pathology, School of Medicine, University of Pecs, Pecs, Hungary
4 Department of Surgical Research and Techniques, School of Medicine, University of Pecs, Pecs, Hungary
5 Department of Organic and Medicinal Chemistry, School of Medicine, University of Pecs, Pecs, Hungary
* Corresponding author. 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 signalling can play a critical role in the development of long-term, high blood pressure-induced cardiac remodelling 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 and results: 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). 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 favourably 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), and PKC 
/βII and 
(P < 0.05).
Conclusion: These data demonstrate that chronic inhibition of PARP induces long-term favourable changes in the most important signalling pathways related to oxidative stress. PARP inhibition also prevents remodelling, preserves systolic function, and delays transition of hypertensive cardiopathy to HF in SHRs.
KEYWORDS PARP-inhibition; SHR; Heart failure; Signal transduction; Echocardiography
Time for primary review: 33 days