Jens Georg Leipziger

Extracellular nucleotide derivatives protect cardiomyctes against hypoxic stress

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  • O Golan, Bar-Ilan University, Israel
  • Y Issan, Bar-Ilan University, Israel
  • A Isak, Bar-Ilan University, Israel
  • Jens Georg Leipziger
  • Bernard Robaye, Institute of Interdisciplinary Research, Institute of Molecular Biology and Medicine, Universite´ Libre de Bruxelles, Gosselies, Belgium
  • Asher Shainberg, Bar-Ilan University, Israel
RATIONALE: Extracellular nucleotides have widespread effects and various cell responses. Whereas the effect of a purine nucleotide (ATP) and a pyrimidine nucleotide (UTP) on myocardial infarction has been examined, the role of different purine and pyrimidine nucleotides and nucleosides in cardioprotection against hypoxic stress has not been reported.

OBJECTIVE: To investigate the role of purine and pyrimidine nucleotides and nucleosides in protective effects in cardiomyocytes subjected to hypoxia.

METHODS AND RESULTS: Rat cultured cardiomyocytes were treated with various extracellular nucleotides and nucleosides, before or during hypoxic stress. The results revealed that GTP or CTP exhibit cardioprotective ability, as revealed by lactate dehydrogenase (LDH) release, by propidium iodide (PI) staining, by cell morphology, and by preserved mitochondrial activity. Pretreatment with various P2 antagonists (suramin, RB-2, or PPADS) did not abolish the cardioprotective effect of the nucleotides. Moreover, P2Y₂ -/- , P2Y₄ -/-, and P2Y₂ -/-/P2Y₄ -/- receptor knockouts mouse cardiomyocytes were significantly protected against hypoxic stress when treated with UTP. These results indicate that the protective effect is not mediated via those receptors. We found that a wide variety of triphosphate and diphosphate nucleotides (TTP, ITP, deoxyGTP, and GDP), provided significant cardioprotective effect. GMP, guanosine, and ribose phosphate provided no cardioprotective effect. Moreover, we observed that tri/di-phosphate alone assures cardioprotection. Treatment with extracellular nucleotides, or with tri/di-phosphate, administered under normoxic conditions or during hypoxic conditions, led to a decrease in reactive oxygen species production.

CONCLUSIONS: Extracellular tri/di-phosphates are apparently the molecule responsible for cardioprotection against hypoxic damage, probably by preventing free radicals formation.

Original languageEnglish
JournalBiochemical Pharmacology
Pages (from-to)1219-1227
Number of pages8
Publication statusPublished - 2011

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