PARP inhibition delays transition of hypertensive cardiopathy to heart failure in spontaneously hypertensive rats

Eva Bartha, Izabella Solti, L. Kereskai, J. Lantos, Eniko Plozer, Klara Magyar, Eszter Szabados, T. Kalai, K. Hideg, R. Halmosi, B. Sümegi, K. Tóth

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Abstract

AimsOxidative 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 resultsSHRs 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 ε (P <0.01), and decreased the phosphorylation of JNK (P <0.05), p-38 MAPK (P <0.01), PKC pan βII and PKC ζ/λ (P <0.01), and PKC α/βII and δ (P <0.05).ConclusionThese 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.

Original languageEnglish
Pages (from-to)501-510
Number of pages10
JournalCardiovascular Research
Volume83
Issue number3
DOIs
Publication statusPublished - Aug 2009

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Poly(ADP-ribose) Polymerases
2-((2-piperidin-1-ylethyl)thio)quinazolin-4(3H)-one
Inbred SHR Rats
Heart Failure
Left Ventricular Function
Oxidative Stress
Research Design
Glycogen Synthase Kinase 3
Hypertrophy
Fibrosis
Cell Death
Theoretical Models
Therapeutics
Survival Rate
Age Groups
Phosphorylation
Blood Pressure
Hypertension
Control Groups
Poly(ADP-ribose) Polymerase Inhibitors

Keywords

  • Echocardiography
  • Heart failure
  • PARP-inhibition
  • SHR
  • Signal transduction

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology

Cite this

PARP inhibition delays transition of hypertensive cardiopathy to heart failure in spontaneously hypertensive rats. / Bartha, Eva; Solti, Izabella; Kereskai, L.; Lantos, J.; Plozer, Eniko; Magyar, Klara; Szabados, Eszter; Kalai, T.; Hideg, K.; Halmosi, R.; Sümegi, B.; Tóth, K.

In: Cardiovascular Research, Vol. 83, No. 3, 08.2009, p. 501-510.

Research output: Contribution to journalArticle

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abstract = "AimsOxidative 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 resultsSHRs 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 ε (P <0.01), and decreased the phosphorylation of JNK (P <0.05), p-38 MAPK (P <0.01), PKC pan βII and PKC ζ/λ (P <0.01), and PKC α/βII and δ (P <0.05).ConclusionThese 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.",
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author = "Eva Bartha and Izabella Solti and L. Kereskai and J. Lantos and Eniko Plozer and Klara Magyar and Eszter Szabados and T. Kalai and K. Hideg and R. Halmosi and B. S{\"u}megi and K. T{\'o}th",
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T1 - PARP inhibition delays transition of hypertensive cardiopathy to heart failure in spontaneously hypertensive rats

AU - Bartha, Eva

AU - Solti, Izabella

AU - Kereskai, L.

AU - Lantos, J.

AU - Plozer, Eniko

AU - Magyar, Klara

AU - Szabados, Eszter

AU - Kalai, T.

AU - Hideg, K.

AU - Halmosi, R.

AU - Sümegi, B.

AU - Tóth, K.

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N2 - AimsOxidative 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 resultsSHRs 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 ε (P <0.01), and decreased the phosphorylation of JNK (P <0.05), p-38 MAPK (P <0.01), PKC pan βII and PKC ζ/λ (P <0.01), and PKC α/βII and δ (P <0.05).ConclusionThese 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.

AB - AimsOxidative 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 resultsSHRs 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 ε (P <0.01), and decreased the phosphorylation of JNK (P <0.05), p-38 MAPK (P <0.01), PKC pan βII and PKC ζ/λ (P <0.01), and PKC α/βII and δ (P <0.05).ConclusionThese 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.

KW - Echocardiography

KW - Heart failure

KW - PARP-inhibition

KW - SHR

KW - Signal transduction

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