title: PARP-inhibitor treatment prevents hypertension induced cardiac remodeling by favorable modulation of heat shock proteins, Akt-1/GSK-3β and several PKC isoforms.
abstract: Spontaneously hypertensive rat (SHR) is a suitable model for studies of the complications of hypertension. It is known that activation of poly(ADP-ribose) polymerase enzyme (PARP) plays an important role in the development of postinfarction as well as long-term hypertension induced heart failure. In this study, we examined whether PARP-inhibitor (L-2286) treatment could prevent the development of hypertensive cardiopathy in SHRs. 6-week-old SHR animals were treated with L-2286 (SHR-L group) or placebo (SHR-C group) for 24 weeks. Wistar-Kyoto rats were used as aged-matched, normotensive controls (WKY group). Echocardiography was performed, brain-derived natriuretic peptide (BNP) activity and blood pressure were determined at the end of the study. We detected the extent of fibrotic areas. The amount of heat-shock proteins (Hsps) and the phosphorylation state of Akt-1(Ser473), glycogen synthase kinase (GSK)-3β(Ser9), forkhead transcription factor (FKHR)(Ser256), mitogen activated protein kinases (MAPKs), and protein kinase C (PKC) isoenzymes were monitored. The elevated blood pressure in SHRs was not influenced by PARP-inhibitor treatment. Systolic left ventricular function and BNP activity did not differ among the three groups. L-2286 treatment decreased the marked left ventricular (LV) hypertrophy which was developed in SHRs. Interstitial collagen deposition was also decreased by L-2286 treatment. The phosphorylation of extracellular signal-regulated kinase (ERK)1/2(Thr183-Tyr185), Akt-1(Ser473), GSK-3β(Ser9), FKHR(Ser256), and PKC ε(Ser729) and the level of Hsp90 were increased, while the activity of PKC α/βII(Thr638/641), ζ/λ(410/403) were mitigated by L-2286 administration. We could detect signs of LV hypertrophy without congestive heart failure in SHR groups. This alteration was prevented by PARP inhibition. Our results suggest that PARP-inhibitor treatment has protective effect already in the early stage of hypertensive myocardial remodeling.
authors.affiliation: First Department of Medicine, Division of Cardiology, University of Pécs, Pécs, Hungary; Szentagothai Janos Research Center, University of Pécs, Medical School, Pécs, Hungary.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Deres
authors.affiliation: First Department of Medicine, Division of Cardiology, University of Pécs, Pécs, Hungary.
authors.forename: Eva
authors.initials: E
authors.lastname: Bartha
authors.affiliation: First Department of Medicine, Division of Cardiology, University of Pécs, Pécs, Hungary.
authors.forename: Anita
authors.initials: A
authors.lastname: Palfi
authors.affiliation: First Department of Medicine, Division of Cardiology, University of Pécs, Pécs, Hungary; Szentagothai Janos Research Center, University of Pécs, Medical School, Pécs, Hungary.
authors.forename: Krisztian
authors.initials: K
authors.lastname: Eros
authors.affiliation: First Department of Medicine, Division of Cardiology, University of Pécs, Pécs, Hungary; Szentagothai Janos Research Center, University of Pécs, Medical School, Pécs, Hungary.
authors.forename: Adam
authors.initials: A
authors.lastname: Riba
authors.affiliation: Department of Surgical Research and Techniques, University of Pécs, Pécs, Hungary.
authors.forename: Janos
authors.initials: J
authors.lastname: Lantos
authors.affiliation: Department of Organic and Medicinal Chemistry, University of Pécs, Pécs, Hungary.
authors.forename: Tamas
authors.initials: T
authors.lastname: Kalai
authors.affiliation: Department of Organic and Medicinal Chemistry, University of Pécs, Pécs, Hungary.
authors.forename: Kalman
authors.initials: K
authors.lastname: Hideg
authors.affiliation: Szentagothai Janos Research Center, University of Pécs, Medical School, Pécs, Hungary; Department of Biochemistry and Medical Chemistry, Medical School, University of Pécs, Pécs, Hungary; MTA-PTE Nuclear-Mitochondrial Interactions Research Group, Pécs, Hungary.
authors.forename: Balazs
authors.initials: B
authors.lastname: Sumegi
authors.affiliation: Department of Biochemistry and Medical Chemistry, Medical School, University of Pécs, Pécs, Hungary; MTA-PTE Nuclear-Mitochondrial Interactions Research Group, Pécs, Hungary.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Gallyas
authors.affiliation: First Department of Medicine, Division of Cardiology, University of Pécs, Pécs, Hungary.
authors.forename: Kalman
authors.initials: K
authors.lastname: Toth
authors.affiliation: First Department of Medicine, Division of Cardiology, University of Pécs, Pécs, Hungary; Szentagothai Janos Research Center, University of Pécs, Medical School, Pécs, Hungary.
authors.forename: Robert
authors.initials: R
authors.lastname: Halmosi
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006333:Heart Failure / Q000209:etiology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D020097:Natriuretic Peptide, Brain / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D015398:Signal Transduction; D000071161:Forkhead Box Protein O1
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D051858:Forkhead Transcription Factors; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D018841:HSP90 Heat-Shock Proteins; D007527:Isoenzymes; D020097:Natriuretic Peptide, Brain; D009419:Nerve Tissue Proteins; D010880:Piperidines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D011493:Protein Kinase C; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; C505456:2-((2-piperidin-1-ylethyl)thio)quinazolin-4(3H)-one; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C494920:Akt1 protein, rat; C000605508:Gsk3b protein, rat