title: PARP inhibition prevents postinfarction myocardial remodeling and heart failure via the protein kinase C/glycogen synthase kinase-3beta pathway.
abstract: The inhibition of glycogen synthase kinase-3beta (GSK-3beta) via phosphorylation by Akt or protein kinase C (PKC), or the activation of mitogen-activated protein kinase (MAPK) cascades can play a pivotal role in left ventricular remodeling following myocardial infarction. Our previous data showed that MAPK and phosphatidylinositol-3-kinase/Akt pathways could be modulated by poly(ADP-ribose)polymerase (PARP) inhibition raising the possibility that cardiac hypertrophic signaling responses may be favorably influenced by PARP inhibitors. A novel PARP inhibitor (L-2286) was tested in a rat model of chronic heart failure following isoproterenol-induced myocardial infarction. Subsequently, cardiac hypertrophy and interstitial collagen deposition were assessed; additionally, mitochondrial enzyme activity and the phosphorylation state of GSK-3beta, Akt, PKC and MAPK cascades were monitored. PARP inhibitor (L-2286) treatment significantly reduced the progression of postinfarction heart failure attenuating cardiac hypertrophy and interstitial fibrosis, and preserving the integrity of respiratory complexes. More importantly, L-2286 repressed the hypertrophy-associated increased phosphorylation of panPKC, PKC alpha/betaII, PKC delta and PKC epsilon, which could be responsible for the activation of the antihypertrophic GSK-3beta. This work provides the first evidence that PARP inhibition beneficially modulates the PKC/GSK-3beta intracellular signaling pathway in a rat model of chronic heart failure identifying a novel drug target to treat heart failure.
authors.affiliation: First Department of Medicine, Division of Cardiology, School of Medicine, University of Pecs, 13 Ifjusag str., H-7624 Pecs, Hungary.
authors.forename: Anita
authors.initials: A
authors.lastname: Palfi
authors.forename: Ambrus
authors.initials: A
authors.lastname: Toth
authors.forename: Katalin
authors.initials: K
authors.lastname: Hanto
authors.forename: Peter
authors.initials: P
authors.lastname: Deres
authors.forename: Eszter
authors.initials: E
authors.lastname: Szabados
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Szereday
authors.forename: Gyozo
authors.initials: G
authors.lastname: Kulcsar
authors.forename: Tamas
authors.initials: T
authors.lastname: Kalai
authors.forename: Kalman
authors.initials: K
authors.lastname: Hideg
authors.forename: Ferenc
authors.initials: F
authors.lastname: Gallyas
authors.forename: Balazs
authors.initials: B
authors.lastname: Sumegi
authors.forename: Kalman
authors.initials: K
authors.lastname: Toth
authors.forename: Robert
authors.initials: R
authors.lastname: Halmosi
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000517:prevention & control; D024061:Collagen Type III / Q000187:drug effects / Q000378:metabolism; D004562:Electrocardiography; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006333:Heart Failure / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D007545:Isoproterenol / Q000009:adverse effects; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D009203:Myocardial Infarction / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D020097:Natriuretic Peptide, Brain / Q000097:blood / Q000187:drug effects; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D020257:Ventricular Remodeling
chemical_list: C505456:2-((2-piperidin-1-ylethyl)thio)quinazolin-4(3H)-one; D024061:Collagen Type III; D004791:Enzyme Inhibitors; D010880:Piperidines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011799:Quinazolines; D020097:Natriuretic Peptide, Brain; D011065:Poly(ADP-ribose) Polymerases; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D007545:Isoproterenol