Original article PARP inhibition prevents postinfarction myocardial remodeling and heart failure via the protein kinase C/glycogen synthase kinase-3β pathway ☆ Anita Palfi a,b , Ambrus Toth b , Katalin Hanto a,b , Peter Deres a,b , Eszter Szabados a , Zoltan Szereday c , Gyozo Kulcsar d , Tamas Kalai d , Kalman Hideg d , Ferenc Gallyas Jr. b , Balazs Sumegi b,e , Kalman Toth a, ⁎ , Robert Halmosi a a First Department of Medicine, Division of Cardiology, School of Medicine, University of Pecs, 13 Ifjusag str., H-7624 Pecs, Hungary b Department of Biochemistry and Medical Chemistry, School of Medicine, University of Pecs, Pecs, Hungary c Department of Dermatology, School of Medicine, University of Pecs, Pecs, Hungary d Department of Organic and Medicinal Chemistry, School of Medicine, University of Pecs, Pecs, Hungary e Research Group for Mitochondrial Function and Mitochondrial Diseases, Hungarian Academy of Sciences, Budapest, Hungary Received 15 September 2005; received in revised form 17 March 2006; accepted 23 March 2006 Available online 23 May 2006 Abstract The inhibition of glycogen synthase kinase-3β (GSK-3β) 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-3β, 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 α/βII, PKC δ and PKC ε, which could be responsible for the activation of the antihypertrophic GSK-3β. This work provides the first evidence that PARP inhibition beneficially modulates the PKC/GSK-3β intracellular signaling pathway in a rat model of chronic heart failure identifying a novel drug target to treat heart failure. © 2006 Elsevier Inc. All rights reserved. Keywords: PARP inhibition; Intracellular signaling; Glycogen synthase kinase-3β; Heart failure; Protein kinase C; Ventricular remodeling 1. Introduction Increased activation of poly(ADP-ribose) polymerase (PARP) enzyme is a crucial step in the development of oxidative stress- induced cell dysfunction and tissue injury [1,2]. Oxidative stress also plays a pathogenic role in chronic heart failure that can be characterized by altered intracellular signaling and gene expression [3–7]. Several studies demonstrated that inhibition of PARP enzyme can efficiently reduce oxidative myocardial damage; nevertheless, little is known about the mechanism of cardioprotection by PARP inhibitors in chronic heart failure [1,2,8]. This molecular mechanism is worth elucidating because Journal of Molecular and Cellular Cardiology 41 (2006) 149 – 159 www.elsevier.com/locate/yjmcc Abbreviations: BNP, B-type natriuretic peptide; BW, body weight; ERK1/2, extracellular signal-regulated kinase; GSK-3β, glycogen synthase kinase-3β; HE, hematoxylin and eosin; ISO, isoproterenol hydrochloride; JNK, c-jun N- terminal kinase; MAPK, mitogen activated protein kinase; NAD + , nicotinamide adenine dinucleotide; NF-κB, nuclear factor-κB; NIH, National Institutes of Health; PARP, poly(ADP-ribose) polymerase; PDC-1α, pyruvate dehydroge- nase complex-1α; PI3K, phosphatidylinositol-3-kinase; PKC, protein kinase C; ROS, reactive oxygen species; SEM, standard error of mean; TBS, Tris-buffered saline; TEF-1, transcriptional enhancer factor-1; TL, length of right tibia; WV, weight of ventricles ☆ List of special characters: β, μ, ±, <. ⁎ Corresponding author. Fax: +36 72 536 146. E-mail address: kalman.toth@aok.pte.hu (K. Toth). 0022-2828/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.yjmcc.2006.03.427