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Late preconditioning elicited by activation of adenosine A(3) receptor in heart: role of NF- kappa B, iNOS and mitochondrial K(ATP) channel.

Abstract
Activation of adenosine A(3) receptor (A(3)AR) protects against ischemia/reperfusion injury in the heart. However, the downstream signaling mechanisms leading to its delayed anti-ischemic effects remain unclear. We hypothesized that A(3)AR stimulation protects the heart via activation of nuclear transcription factor kappa B (NF-kappa B) and synthesis of inducible nitric oxide synthase (iNOS). Mice were treated with selective A(3)AR agonist, N(6)-(3-iodobenzyl) adenosine-5;-N-methyluronamide (IB-MECA). Twenty-four h later, hearts were perfused in Langendorff mode and subjected to 30 min of global ischemia and 30 min of reperfusion. IB-MECA caused post-ischemic reduction in necrosis and improvement in myocardial performance which was abolished by A(3)AR antagonist, MRS1191. Electrophoretic mobility shift assay demonstrated increased NF-kappa B binding in nuclear extracts following A(3)AR stimulation, which was diminished by MRS1191 and NF-kappa B inhibitor, pyrrolidinediethyldithiocarbamate (PDTC). The cardioprotection was abrogated by PDTC and targeted ablation of p50 subunit of NF-kappa B in mice. The inhibition of iNOS with S-methylisothiourea and targeted disruption of the iNOS gene also abolished the protective effect of A(3)AR stimulation. Expression of iNOS mRNA and NO production were enhanced after 6 and 24 h respectively of IB-MECA treatment. MRS1191 and PDTC blocked IB-MECA induced NO production after A(3)AR stimulation. MitoK(ATP) channel blocker, 5-hydroxydecanoate abolished the protective effect of A(3)AR. For the first time, we have provided direct evidence of an essential role of NF- kappa B activation and iNOS in A(3)AR-induced late preconditioning. Selective activation of A(3)AR with IB-MECA can be used to trigger long-lasting ischemic protection in the heart.
AuthorsTing C Zhao, Rakesh C Kukreja
JournalJournal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 34 Issue 3 Pg. 263-77 (Mar 2002) ISSN: 0022-2828 [Print] England
PMID11945020 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
CopyrightCopyright 2002 Academic Press.
Chemical References
  • NF-kappa B
  • Potassium Channels
  • RNA, Messenger
  • Receptor, Adenosine A3
  • Receptors, Purinergic P1
  • N(6)-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Adenosine
Topics
  • Adenosine (analogs & derivatives, pharmacology)
  • Animals
  • Electrophoretic Mobility Shift Assay
  • Heart (drug effects)
  • Ischemic Preconditioning, Myocardial
  • Male
  • Mice
  • Mice, Inbred ICR
  • Mitochondria, Heart (metabolism)
  • Myocardium (metabolism, pathology)
  • NF-kappa B (metabolism)
  • Nitric Oxide Synthase (antagonists & inhibitors, genetics, metabolism)
  • Nitric Oxide Synthase Type II
  • Potassium Channels (metabolism)
  • RNA, Messenger (genetics, metabolism)
  • Receptor, Adenosine A3
  • Receptors, Purinergic P1 (metabolism)
  • Reperfusion Injury (metabolism, prevention & control)
  • Reverse Transcriptase Polymerase Chain Reaction

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