Role of poly(ADP-ribose) polymerase activation in endotoxin-induced cardiac collapse in rodents
Pacher, P., Cziraki, A., Mabley, J.G., Liaudet, L., Papp, L and Szabo, C. (2002) Role of poly(ADP-ribose) polymerase activation in endotoxin-induced cardiac collapse in rodents Biochemical pharmacology, 64 (12). pp. 1785-1791. ISSN 0006-2952
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Official URL: http://dx.doi.org/10.1016/S0006-2952(02)01421-1
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.
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