Role of poly(ADP-ribose) polymerase activation in endotoxin-induced cardiac collapse in rodents

Pál Pacher, Attila Cziráki, Jon G. Mabley, Lucas Liaudet, Lajos Papp, Csaba Szabo

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1785-1791
Number of pages7
JournalBiochemical Pharmacology
Volume64
Issue number12
DOIs
StatePublished - Dec 15 2002
Externally publishedYes

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Poly(ADP-ribose) Polymerases
Endotoxins
Rodentia
Chemical activation
Cardiovascular System
Cardiovascular system
Lipopolysaccharides
Shock
Arterial Pressure
Genetic Suppression
Reactive Nitrogen Species
Septic Shock
Oxidants
Tachycardia
Knockout Mice
Reactive Oxygen Species
Blood pressure
Salts
Pharmacology
Rats

Keywords

  • Cardiac collapse
  • Cardiac function
  • Endotoxin
  • Poly(ADP-ribose) polymerase
  • Shock

ASJC Scopus subject areas

  • Pharmacology

Cite this

Role of poly(ADP-ribose) polymerase activation in endotoxin-induced cardiac collapse in rodents. / Pacher, Pál; Cziráki, Attila; Mabley, Jon G.; Liaudet, Lucas; Papp, Lajos; Szabo, Csaba.

In: Biochemical Pharmacology, Vol. 64, No. 12, 15.12.2002, p. 1785-1791.

Research output: Contribution to journalArticle

Pacher, Pál ; Cziráki, Attila ; Mabley, Jon G. ; Liaudet, Lucas ; Papp, Lajos ; Szabo, Csaba. / Role of poly(ADP-ribose) polymerase activation in endotoxin-induced cardiac collapse in rodents. In: Biochemical Pharmacology. 2002 ; Vol. 64, No. 12. pp. 1785-1791.
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