Tags

Type your tag names separated by a space and hit enter

PARP inhibition delays transition of hypertensive cardiopathy to heart failure in spontaneously hypertensive rats.
Cardiovasc Res. 2009 Aug 01; 83(3):501-10.CR

Abstract

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-3beta (P < 0.01), ERK 1/2 (P < 0.01), and PKC epsilon (P < 0.01), and decreased the phosphorylation of JNK (P < 0.05), p-38 MAPK (P < 0.01), PKC pan betaII and PKC zeta/lambda (P < 0.01), and PKC alpha/betaII and delta (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.

Authors+Show Affiliations

First Department of Medicine, Division of Cardiology, School of Medicine, University of Pecs, 13 Ifjusag St., Pecs H-7624, Hungary.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19443425

Citation

Bartha, Eva, et al. "PARP Inhibition Delays Transition of Hypertensive Cardiopathy to Heart Failure in Spontaneously Hypertensive Rats." Cardiovascular Research, vol. 83, no. 3, 2009, pp. 501-10.
Bartha E, Solti I, Kereskai L, et al. PARP inhibition delays transition of hypertensive cardiopathy to heart failure in spontaneously hypertensive rats. Cardiovasc Res. 2009;83(3):501-10.
Bartha, E., Solti, I., Kereskai, L., Lantos, J., Plozer, E., Magyar, K., Szabados, E., Kálai, T., Hideg, K., Halmosi, R., Sumegi, B., & Toth, K. (2009). PARP inhibition delays transition of hypertensive cardiopathy to heart failure in spontaneously hypertensive rats. Cardiovascular Research, 83(3), 501-10. https://doi.org/10.1093/cvr/cvp144
Bartha E, et al. PARP Inhibition Delays Transition of Hypertensive Cardiopathy to Heart Failure in Spontaneously Hypertensive Rats. Cardiovasc Res. 2009 Aug 1;83(3):501-10. PubMed PMID: 19443425.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - PARP inhibition delays transition of hypertensive cardiopathy to heart failure in spontaneously hypertensive rats. AU - Bartha,Eva, AU - Solti,Izabella, AU - Kereskai,Laszlo, AU - Lantos,Janos, AU - Plozer,Eniko, AU - Magyar,Klara, AU - Szabados,Eszter, AU - Kálai,Tamás, AU - Hideg,Kálmán, AU - Halmosi,Robert, AU - Sumegi,Balazs, AU - Toth,Kalman, Y1 - 2009/05/14/ PY - 2009/5/16/entrez PY - 2009/5/16/pubmed PY - 2009/9/18/medline SP - 501 EP - 10 JF - Cardiovascular research JO - Cardiovasc Res VL - 83 IS - 3 N2 - 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-3beta (P < 0.01), ERK 1/2 (P < 0.01), and PKC epsilon (P < 0.01), and decreased the phosphorylation of JNK (P < 0.05), p-38 MAPK (P < 0.01), PKC pan betaII and PKC zeta/lambda (P < 0.01), and PKC alpha/betaII and delta (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. SN - 1755-3245 UR - https://www.unboundmedicine.com/medline/citation/19443425/PARP_inhibition_delays_transition_of_hypertensive_cardiopathy_to_heart_failure_in_spontaneously_hypertensive_rats_ L2 - https://academic.oup.com/cardiovascres/article-lookup/doi/10.1093/cvr/cvp144 DB - PRIME DP - Unbound Medicine ER -