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Enhanced ADP-ribosylation and its diminution by lipoamide after ischemia-reperfusion in perfused rat heart.

Abstract
Poly-ADP-ribose polymerase (PARP) is considered to play an important role in oxidative cell damage. We assumed that ischemia-reperfusion resulting from the increasing reactive oxygen species (ROS) can lead to the activation of endogenous mono- and poly-ADP-ribosylation reactions and that the reduction of ROS level by lipoamide, a less known antioxidant, can reverse these unfavorable processes. Experiments were performed on isolated Langendorff hearts subjected to 60-min ischemia followed by reperfusion. ROS, malondialdehyde, deoxyribonucleic acid (DNA) breaks, and NAD+ content were assayed in the hearts, and the ADP-ribosylation of cytoplasmic and nuclear proteins were determined by Western blot assay. Ischemia-reperfusion caused a moderate (30.2 +/- 8%) increase in ROS production determined by the dihydrorhodamine 123 method and significantly increased the malondialdehyde production (from < 1 to 23 +/- 2.7 nmol/ml), DNA damage (undamaged DNA decreased from 71 +/- 7% to 23.1 +/- 5%), and NAD+ catabolism. In addition, ischemia-reperfusion activated the mono-ADP-ribosylation of GRP78 and the self-ADP-ribosylation of the nuclear PARP. The perfusion of hearts with lipoamide significantly decreased the ischemia-reperfusion-induced cell membrane damage determined by enzyme release (LDH, CK, and GOT), decreased the ROS production, reduced the malondialdehyde production to 5.5 +/- 2.4 nmol/ml, abolished DNA damage, and reduced NAD+ catabolism. The ischemia-reperfusion-induced activation of poly- and mono-ADP-ribosylation reactions were also reverted by lipoamide. In isolated rat heart mitochondria, dihydrolipoamide was found to be a better antioxidant than dihydrolipoic acid. Ischemia-reperfusion by ROS overproduction and increasing DNA breaks activates PARP leading to accelerated NAD+ catabolism, impaired energy metabolism, and cell damage. Lipoamide by reducing ROS levels halts PARP activation and membrane damage and improves the recovery of postischemic myocardium.
AuthorsE Szabados, G M Fischer, F Gallyas Jr, G Kispal, B Sumegi
JournalFree radical biology & medicine (Free Radic Biol Med) Vol. 27 Issue 9-10 Pg. 1103-13 (Nov 1999) ISSN: 0891-5849 [Print] United States
PMID10569643 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antioxidants
  • Proteins
  • Reactive Oxygen Species
  • NAD
  • Adenosine Diphosphate Ribose
  • dihydrolipoamide
  • Thioctic Acid
  • dihydrolipoic acid
  • lipoamide
  • ADP Ribose Transferases
  • Poly(ADP-ribose) Polymerases
Topics
  • ADP Ribose Transferases
  • Adenosine Diphosphate Ribose (metabolism)
  • Animals
  • Antioxidants (pharmacology)
  • DNA Damage
  • Enzyme Activation (drug effects)
  • In Vitro Techniques
  • Lipid Peroxidation (drug effects)
  • Male
  • Mitochondria, Heart (drug effects, metabolism)
  • Myocardial Reperfusion Injury (drug therapy, metabolism)
  • NAD (metabolism)
  • Perfusion
  • Poly(ADP-ribose) Polymerases (metabolism)
  • Proteins (metabolism)
  • Rats
  • Rats, Wistar
  • Reactive Oxygen Species (metabolism)
  • Thioctic Acid (analogs & derivatives, pharmacology)

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