TY - JOUR
T1 - Role of poly(ADP-ribose) polymerase activation in endotoxin-induced cardiac collapse in rodents
AU - Pacher, Pál
AU - Cziráki, Attila
AU - Mabley, Jon G.
AU - Liaudet, Lucas
AU - Papp, Lajos
AU - Szabó, Csaba
N1 - Funding Information:
This work was supported by a grant from the National Institutes of Health (R01 HL 59266) to C.S., and a grant from the Hungarian Ministry for Health and Education (ETT 351/2002) to A.C.
PY - 2002/12/15
Y1 - 2002/12/15
N2 - 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 55mg/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.
AB - 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 55mg/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.
KW - Cardiac collapse
KW - Cardiac function
KW - Endotoxin
KW - Poly(ADP-ribose) polymerase
KW - Shock
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U2 - 10.1016/S0006-2952(02)01421-1
DO - 10.1016/S0006-2952(02)01421-1
M3 - Article
C2 - 12445868
AN - SCOPUS:0037114463
SN - 0006-2952
VL - 64
SP - 1785
EP - 1791
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 12
ER -