title: PARP inhibition delays transition of hypertensive cardiopathy to heart failure in spontaneously hypertensive rats.
abstract: OBJECTIVE
  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.
  
  
  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).
  
  
  CONCLUSIONS
  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.affiliation: First Department of Medicine, Division of Cardiology, School of Medicine, University of Pecs, 13 Ifjusag St., Pecs H-7624, Hungary.
authors.forename: Eva
authors.initials: E
authors.lastname: Bartha
authors.forename: Izabella
authors.initials: I
authors.lastname: Solti
authors.forename: Laszlo
authors.initials: L
authors.lastname: Kereskai
authors.forename: Janos
authors.initials: J
authors.lastname: Lantos
authors.forename: Eniko
authors.initials: E
authors.lastname: Plozer
authors.forename: Klara
authors.initials: K
authors.lastname: Magyar
authors.forename: Eszter
authors.initials: E
authors.lastname: Szabados
authors.forename: Tamás
authors.initials: T
authors.lastname: Kálai
authors.forename: Kálmán
authors.initials: K
authors.lastname: Hideg
authors.forename: Robert
authors.initials: R
authors.lastname: Halmosi
authors.forename: Balazs
authors.initials: B
authors.lastname: Sumegi
authors.forename: Kalman
authors.initials: K
authors.lastname: Toth
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005355:Fibrosis; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006333:Heart Failure / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D006973:Hypertension / Q000150:complications* / Q000201:enzymology / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology; D007527:Isoenzymes / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D020097:Natriuretic Peptide, Brain / Q000097:blood; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C505456:2-((2-piperidin-1-ylethyl)thio)quinazolin-4(3H)-one; D002317:Cardiovascular Agents; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D010880:Piperidines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011799:Quinazolines; D020097:Natriuretic Peptide, Brain; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C494920:Akt1 protein, rat; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3