Activation of poly(ADP-ribose) polymerase contributes to development of doxorubicin-induced heart failure.
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.
Pacher
P
P
Inotek Corporation, Beverly, Massachusetts 01915, USA.
Liaudet
L
L
Bai
P
P
Virag
L
L
Mabley
J G
JG
Haskó
G
G
Szabó
C
C
D000208:Acute Disease; D000818:Animals; D000903:Antibiotics, Antineoplastic; D003402:Creatine Kinase / Q000378:metabolism; D004317:Doxorubicin; D004789:Enzyme Activation / Q000187:drug effects; D006333:Heart Failure / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics* / Q000378:metabolism*; D016019:Survival Analysis; D016277:Ventricular Function, Left / Q000235:genetics
D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D007770:L-Lactate Dehydrogenase; D011065:Poly(ADP-ribose) Polymerases; D003402:Creatine Kinase; D008666:Metalloendopeptidases