BGP-15, a nicotinic amidoxime derivate protecting heart from ischemia reperfusion injury through modulation of poly(ADP-ribose) polymerase

Eszter Szabados, Peter Literati-Nagy, Beatrix Farkas, B. Sümegi

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

The protective effect of O-(3-piperidino-2-hydroxy-1-propyl)nicotinic amidoxime (BGP-15) against ischemia-reperfusion-induced injury was studied in the Langendorff heart perfusion system. To understand the molecular mechanism of the cardioprotection, the effect of BGP-15 on ischemic-reperfusion-induced reactive oxygen species (ROS) formation, lipid peroxidation single-strand DNA break formation, NAD+ catabolism, and endogenous ADP-ribosylation reactions were investigated. These studies showed that BGP-15 significantly decreased leakage of lactate dehydrogenase, creatine kinase, and aspartate aminotransferase in reperfused hearts, and reduced the rate of NAD+ catabolism. In addition, BGP-15 dramatically decreased the ischemia- reperfusion-induced self-ADP-ribosylation of nuclear poly(ADP-ribose) polymerase(PARP) and the mono-ADP-ribosylation of an endoplasmic reticulum chaperone GRP78. These data raise the possibility that BGP-15 may have a direct inhibitory effect on PARP. This hypothesis was tested on isolated enzyme, and kinetic analysis showed a mixed-type (noncompetitive) inhibition with a K(i) = 57 ± 6 μM. Furthermore, BGP-15 decreased levels of ROS, lipid peroxidation, and single-strand DNA breaks in reperfused hearts. These data suggest that PARP may be an important molecular target of BGP-15 and that BGP-15 decreases ROS levels and cell injury during ischemia-reperfusion in the heart by inhibiting PARP activity. (C) 2000 Elsevier Science Inc.

Original languageEnglish
Pages (from-to)937-945
Number of pages9
JournalBiochemical Pharmacology
Volume59
Issue number8
DOIs
Publication statusPublished - Apr 15 2000

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Reperfusion Injury
Adenosine Diphosphate
Modulation
Poly(ADP-ribose) Polymerases
Single-Stranded DNA Breaks
Reactive Oxygen Species
NAD
Lipid Peroxidation
Reperfusion
Lipids
amidoxime
BGP 15
DNA
Creatine Kinase
Aspartate Aminotransferases
L-Lactate Dehydrogenase
Endoplasmic Reticulum
Ischemia
Perfusion
Heart Rate

Keywords

  • BGP-15
  • Cell damage
  • Chaperone
  • Free radicals
  • GRP78
  • Heart perfusion
  • Ischemia-reperfusion
  • Lipid peroxidation
  • Poly(ADP-ribose) polymerase
  • Reactive oxygen species
  • Signal

ASJC Scopus subject areas

  • Pharmacology

Cite this

BGP-15, a nicotinic amidoxime derivate protecting heart from ischemia reperfusion injury through modulation of poly(ADP-ribose) polymerase. / Szabados, Eszter; Literati-Nagy, Peter; Farkas, Beatrix; Sümegi, B.

In: Biochemical Pharmacology, Vol. 59, No. 8, 15.04.2000, p. 937-945.

Research output: Contribution to journalArticle

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