Extracellular nucleotide derivatives protect cardiomyocytes against hypoxic stress.

Abstract

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.

• Authors: O Golan, Y Issan, A Isak, J Leipziger, B Robaye, A Shainberg
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 81 Issue 10 Pg. 1219-27 (May 15 2011) ISSN: 1873-2968 [Electronic] England
• PMID: 21376706 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Antioxidants
• Chelating Agents
• Purine Nucleosides
• Purine Nucleotides
• Purinergic Antagonists
• Pyrimidine Nucleosides
• Pyrimidine Nucleotides
• Reactive Oxygen Species
• Receptors, Purinergic P2
• Receptors, Purinergic P2Y2
• purinoceptor P2Y4
• Uridine Triphosphate

Topics

• Animals
• Antioxidants (pharmacology)
• Cell Hypoxia
• Cell Survival (drug effects)
• Cells, Cultured
• Chelating Agents (pharmacology)
• Extracellular Fluid (metabolism)
• Gene Knockout Techniques
• Mice
• Mice, Inbred C57BL
• Mitochondria, Heart (physiology)
• Myocytes, Cardiac (cytology, drug effects, metabolism)
• Purine Nucleosides (metabolism, pharmacology)
• Purine Nucleotides (metabolism, pharmacology)
• Purinergic Antagonists (pharmacology)
• Pyrimidine Nucleosides (metabolism, pharmacology)
• Pyrimidine Nucleotides (metabolism, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Reactive Oxygen Species (metabolism)
• Receptors, Purinergic P2 (genetics)
• Receptors, Purinergic P2Y2 (genetics)
• Stress, Physiological
• Uridine Triphosphate (physiology)