Role of poly(ADP-ribose) polymerase activation in endotoxin-induced cardiac collapse in rodents.
Reactive oxygen and nitrogen species are overproduced in the cardiovascular system during circulatory shock. Oxidant-induced cell injury involves the activation of poly(ADP-ribose) polymerase (PARP). Using a dual approach of PARP-1 suppression, by genetic deletion or pharmacological inhibition with the new potent phenanthridinone PARP inhibitor PJ34 [the hydrochloride salt of N-(oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethylacetamide], we studied whether the impaired cardiac function in endotoxic shock is dependent upon the PARP pathway. Escherichia coli endotoxin (lipopolysaccharide, LPS) at 55 mg/kg, i.p., induced a severe depression of the systolic and diastolic contractile function, tachycardia, and a reduction in mean arterial blood pressure in both rats and mice. Treatment with PJ34 significantly improved cardiac function and increased the survival of rodents. In addition, LPS-induced depression of left ventricular performance was significantly less pronounced in PARP-1 knockout mice (PARP(-/-)) as compared with their wild-type littermates (PARP(+/+)). Thus, PARP activation in the cardiovascular system is an important contributory factor to the cardiac collapse and death associated with endotoxin shock.
Pacher
Pál
P
Inotek Corporation, Suite 419E, 100 Cummings Center, Beverly, MA 01915, USA.
Cziráki
Attila
A
Mabley
Jon G
JG
Liaudet
Lucas
L
Papp
Lajos
L
Szabó
Csaba
C
D000818:Animals; D003643:Death; D004195:Disease Models, Animal; D004347:Drug Interactions; D004731:Endotoxins / Q000633:toxicity*; D004789:Enzyme Activation; D017353:Gene Deletion; D006331:Heart Diseases / Q000139:chemically induced / Q000201:enzymology* / Q000401:mortality; D006334:Heart Function Tests; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D010616:Phenanthrenes / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
D004731:Endotoxins; D008070:Lipopolysaccharides; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases