Activation of poly(ADP-ribose) polymerase contributes to development of doxorubicin-induced heart failure
Détails
ID Serval
serval:BIB_39EA6CCC5917
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Activation of poly(ADP-ribose) polymerase contributes to development of doxorubicin-induced heart failure
Périodique
Journal of Pharmacology and Experimental Therapeutics
ISSN
0022-3565 (Print)
Statut éditorial
Publié
Date de publication
03/2002
Volume
300
Numéro
3
Pages
862-7
Notes
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S. --- Old month value: Mar
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S. --- Old month value: Mar
Résumé
Activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) by oxidant-mediated DNA damage is an important pathway of cell dysfunction and tissue injury in conditions associated with oxidative stress. Increased oxidative stress is a major factor implicated in the cardiotoxicity of doxorubicin (DOX), a widely used antitumor anthracycline antibiotic. Thus, we hypothesized that the activation of PARP may contribute to the DOX-induced cardiotoxicity. Using a dual approach of PARP-1 suppression, by genetic deletion or pharmacological inhibition with the phenanthridinone PARP inhibitor PJ34, we now demonstrate the role of PARP in the development of cardiac dysfunction induced by DOX. PARP-1+/+ and PARP-1-/- mice received a single injection of DOX (25 mg/kg i.p). Five days after DOX administration, left ventricular performance was significantly depressed in PARP-1+/+ mice, but only to a smaller extent in PARP-1-/- ones. Similar experiments were conducted in BALB/c mice treated with PJ34 or vehicle. Treatment with a PJ34 significantly improved cardiac dysfunction and increased the survival of the animals. In addition PJ34 significantly reduced the DOX-induced increase in the serum lactate dehydrogenase and creatine kinase activities but not metalloproteinase activation in the heart. Thus, PARP activation contributes to the cardiotoxicity of DOX. PARP inhibitors may exert protective effects against the development of severe cardiac complications associated with the DOX treatment.
Mots-clé
Acute Disease
Animals
*Antibiotics, Antineoplastic
Creatine Kinase/metabolism
*Doxorubicin
Enzyme Activation/drug effects
Heart Failure, Congestive/*chemically induced/pathology/physiopathology
Hemodynamic Processes/drug effects
L-Lactate Dehydrogenase/metabolism
Male
Metalloendopeptidases/metabolism
Mice
Mice, Inbred BALB C
Mice, Knockout
Poly(ADP-ribose) Polymerases/*genetics/*metabolism
Survival Analysis
Ventricular Function, Left/genetics
Pubmed
Web of science
Création de la notice
24/01/2008 17:00
Dernière modification de la notice
20/08/2019 13:29