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Cardiovascular Research 2003 57(3):715-726; doi:10.1016/S0008-6363(02)00738-1
© 2003 by European Society of Cardiology
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Copyright © 2003, European Society of Cardiology

Effects of A1 adenosine receptor overexpression on normoxic and post-ischemic gene expression

Kevin J Ashtona, Kirsty Holmgrena, Jason Pearta, Amy R Lankfordb, G Paul Matherneb, Sean Grimmondc and John P Headricka,*

aHeart Foundation Research Centre, Griffith University Gold Coast Campus, Southport, Queensland, QLD 4217, Australia
bDepartment of Pediatrics and the Cardiovascular Research Center, University of Virginia Health Sciences Center, Charlottesville, VA, USA
cInstitute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia

* Corresponding author. Tel.: +61-7-5552-8292; fax: +61-7-5552-8802. j.headrick{at}mailbox.gu.edu.au

Objectives: To identify potential molecular genetic determinants of cardiovascular ischemic tolerance in wild-type and transgenic hearts overexpressing A1 adenosine receptors (A1ARs). Methods: cDNA microarrays were used to explore expression of 1824 genes in wild-type hearts and ischemia-tolerant mouse hearts overexpressing A1ARs. Results: Overexpression of A1ARs reduced post-ischemic contractile dysfunction, limited arrhythmogenesis, and reduced necrosis by ~80% in hearts subjected to 30 min global ischemia 60 min reperfusion. Cardioprotection was abrogated by acute A1AR antagonism, and only a small number (19) of genes were modified by A1AR overexpression in normoxic hearts. Ischemia-reperfusion significantly altered expression of 75 genes in wild-type hearts (14 induced, 61 down-regulated), including genes for metabolic enzymes, structural/motility proteins, cell signaling proteins, defense/growth proteins, and regulators of transcription and translation. A1AR overexpression reversed the majority of gene down-regulation whereas gene induction was generally unaltered. Additionally, genes involved in cell defence, signaling and gene expression were selectively modified by ischemia in transgenic hearts (33 induced, 10 down-regulated), possibly contributing to the protected phenotype. Real-time PCR verified changes in nine selected genes, revealing concordance with array data. Transcription of the A1AR gene was also modestly reduced post-ischemia, consistent with impaired functional sensitivity to A1AR stimulation Conclusions: Data are presented regarding the early post-ischemic gene profile of intact heart. Reduced A1AR transcription is observed which may contribute to poor outcome from ischemia. A1AR overexpression selectively modifies post-ischemic gene expression, potentially contributing to ischemic-tolerance.

KEYWORDS Adenosine; Gene expression; Ischemia; Receptors; Reperfusion


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