title: Effect of L-2286, a poly(ADP-ribose)polymerase inhibitor and enalapril on myocardial remodeling and heart failure.
abstract: Increased activation of poly(ADP-ribose) polymerase (PARP) enzyme has been implicated in the pathogenesis of acute and chronic myocardial dysfunction. We have demonstrated the protective effect of PARP inhibitors against postinfarction myocardial remodeling and heart failure. The primary aim of our recent work was to compare the effect and efficacy of a potent PARP-inhibitor (L-2286) to enalapril, a widely used angiotensin-converting enzyme (ACE) inhibitor. in experimental heart failure model. Both L-2286 and enalapril were tested in a rat model of chronic heart failure after isoproterenol-induced myocardial infarction. After a 12-week treatment period, echocardiography was performed, cardiac hypertrophy and interstitial collagen deposition were assessed, and the phosphorylation state of Akt-1/GSK-3beta pathway as well as the PKC and MAPK kinases were determined. Both PARP and ACE inhibition reduced the progression of postinfarction heart failure by attenuating cardiac hypertrophy and interstitial fibrosis. More importantly, PARP inhibition increased the activity of the prosurvival signal transduction factors (Akt-1/GSK-3beta pathway, PKCepsilon). Due to these effects, L-2286 improved the systolic left ventricular function. Enalapril treatment exerted a similar, but weaker protective effect against postinfarction myocardial remodeling and heart failure. In conclusion, we demonstrated in an experimental heart failure model that L-2286 decreased the postinfarction myocardial remodeling more effectively than enalapril treatment.
authors.affiliation: 1st Department of Medicine, Division of Cardiology, School of Medicine, University of Pecs, Pecs, Hungary.
authors.forename: Eva
authors.initials: E
authors.lastname: Bartha
authors.forename: Gyongyi N
authors.initials: GN
authors.lastname: Kiss
authors.forename: Endre
authors.initials: E
authors.lastname: Kalman
authors.forename: Gyozo
authors.initials: G
authors.lastname: Kulcsár
authors.forename: Tamás
authors.initials: T
authors.lastname: Kálai
authors.forename: Kálmán
authors.initials: K
authors.lastname: Hideg
authors.forename: Tamas
authors.initials: T
authors.lastname: Habon
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: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D006332:Cardiomegaly / Q000517:prevention & control; D004195:Disease Models, Animal; D004452:Echocardiography; D004656:Enalapril / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005355:Fibrosis / Q000517:prevention & control; D006333:Heart Failure / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D008297:Male; D009203:Myocardial Infarction / Q000150:complications / Q000503:physiopathology; D010880:Piperidines / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: C505456:2-((2-piperidin-1-ylethyl)thio)quinazolin-4(3H)-one; D000806:Angiotensin-Converting Enzyme Inhibitors; D004791:Enzyme Inhibitors; D010880:Piperidines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011799:Quinazolines; D004656:Enalapril