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: Anita Palfi, Ambrus Toth, Katalin Hanto, Peter Deres, Eszter Szabados, Zoltan Szereday, Gyozo Kulcsar, Tamas Kalai, Kalman Hideg, Ferenc Gallyas Jr, Balazs Sumegi, Kalman Toth, Robert Halmosi
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 41 Issue 1 Pg. 149-59 (Jul 2006) ISSN: 0022-2828 [Print] England
• PMID: 16716347 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-((2-piperidin-1-ylethyl)thio)quinazolin-4(3H)-one
• Collagen Type III
• Enzyme Inhibitors
• Piperidines
• Poly(ADP-ribose) Polymerase Inhibitors
• Quinazolines
• Natriuretic Peptide, Brain
• Poly(ADP-ribose) Polymerases
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, rat
• Protein Kinase C
• Mitogen-Activated Protein Kinases
• Glycogen Synthase Kinase 3
• Isoproterenol

Topics

• Animals
• Cardiomegaly (prevention & control)
• Collagen Type III (drug effects, metabolism)
• Electrocardiography
• Enzyme Inhibitors (pharmacology)
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Heart Failure (chemically induced, metabolism, prevention & control)
• Isoproterenol (adverse effects)
• Male
• Mitogen-Activated Protein Kinases (drug effects, metabolism)
• Myocardial Infarction (complications, metabolism, physiopathology)
• Natriuretic Peptide, Brain (blood, drug effects)
• Phosphorylation
• Piperidines (pharmacology)
• Poly(ADP-ribose) Polymerase Inhibitors
• Poly(ADP-ribose) Polymerases (metabolism)
• Protein Kinase C (metabolism)
• Quinazolines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction
• Ventricular Remodeling