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Involvement of uracil nucleotides in protection of cardiomyocytes from hypoxic stress.

Abstract
Cardiomyocytes express one or more subtypes of P2 receptors for extracellular nucleotides. P2 purinoceptors, which are activated by nucleotides, are classified as P2X or P2Y: P2X receptors are ligand-gated intrinsic ion channels, and P2Y receptors are G protein-coupled receptors. Extracellular pyrimidine and purine nucleotides are released from the heart during hypoxia. Although the cardioprotective effects of purines acting via purinoceptors were studied intensively, the physiological role of uracil nucleotide-responsive P2Y2, P2Y4, P2Y6, and P2Y14 receptors is still unclear, especially in the cardiovascular system. This study revealed that uridine-5'-triphosphate (UTP) protected cultured rat cardiomyocytes during hypoxia and explored the UTP signaling pathway leading to this cardioprotection. We found that UTP, but not UDP or uridine, significantly reduced cardiomyocyte death induced by hypoxia. Incubation with UTP for 1 h, before exposure to hypoxic conditions, protected the cells 24 h later. The cardioprotective effect of UTP was reduced in the presence of the P2 antagonist suramin. In addition, UTP caused a transient increase of [Ca2+]i in cardiomyocytes. Pyridoxal-5'-phosphate-6-azophenyl-2,4-disulfonate (PPADS) or Reactive blue 2 (RB-2), other antagonists of P2 receptors, abolished the [Ca2+]i elevation caused by UTP. We used various inhibitors of the Ca2+ signaling pathway to show that UTP elevated levels of [Ca2+]i, originating from intracellular sources, via activation of phospholipase C and the IP3 receptor. Interestingly, these inhibitors of the Ca2+ signaling pathway did not prevent the immediate protective effect caused by UTP. Although mitochondrial KATP channels are involved in other preconditioning mediator pathways, the involvement of these channels in the cardioprotective effect induced by UTP was ruled out, because 5-hydroxydecanoic acid (5-HD), a specific inhibitor of these channels, did not prevent the protection.
AuthorsSmadar Yitzhaki, Vladimir Shneyvays, Kenneth A Jacobson, Asher Shainberg
JournalBiochemical pharmacology (Biochem Pharmacol) Vol. 69 Issue 8 Pg. 1215-23 (Apr 15 2005) ISSN: 0006-2952 [Print] England
PMID15794942 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Cardiotonic Agents
  • Purinergic P2 Receptor Antagonists
  • Receptors, Purinergic P2
  • Triazines
  • Uracil Nucleotides
  • pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid
  • Uridine Diphosphate
  • Cibacron Blue F 3GA
  • Pyridoxal Phosphate
  • Suramin
  • Adenosine Triphosphate
  • L-Lactate Dehydrogenase
  • Type C Phospholipases
  • Calcium
  • Uridine Triphosphate
  • Uridine
Topics
  • Adenosine Triphosphate (analysis, metabolism)
  • Animals
  • Blotting, Western
  • Calcium (metabolism)
  • Calcium Signaling (drug effects)
  • Cardiotonic Agents (metabolism)
  • Cell Hypoxia
  • Cells, Cultured
  • Enzyme Activation
  • Immunohistochemistry
  • L-Lactate Dehydrogenase (analysis, metabolism)
  • Myocytes, Cardiac (metabolism)
  • Purinergic P2 Receptor Antagonists
  • Pyridoxal Phosphate (analogs & derivatives, pharmacology)
  • Rats
  • Receptors, Purinergic P2 (drug effects, metabolism)
  • Stress, Physiological
  • Suramin (pharmacology)
  • Time Factors
  • Triazines (pharmacology)
  • Type C Phospholipases (metabolism)
  • Uracil Nucleotides (metabolism)
  • Uridine (metabolism)
  • Uridine Diphosphate (metabolism)
  • Uridine Triphosphate (metabolism)

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