Effects of A1 adenosine receptor overexpression on normoxic and post-ischemic gene expression.
OBJECTIVE
To identify potential molecular genetic determinants of cardiovascular ischemic tolerance in wild-type and transgenic hearts overexpressing A(1) adenosine receptors (A(1)ARs).


METHODS
cDNA microarrays were used to explore expression of 1824 genes in wild-type hearts and ischemia-tolerant mouse hearts overexpressing A(1)ARs.


RESULTS
Overexpression of A(1)ARs reduced post-ischemic contractile dysfunction, limited arrhythmogenesis, and reduced necrosis by approximately 80% in hearts subjected to 30 min global ischemia 60 min reperfusion. Cardioprotection was abrogated by acute A(1)AR antagonism, and only a small number (19) of genes were modified by A(1)AR 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. A(1)AR 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 A(1)AR gene was also modestly reduced post-ischemia, consistent with impaired functional sensitivity to A(1)AR stimulation


CONCLUSIONS
Data are presented regarding the early post-ischemic gene profile of intact heart. Reduced A(1)AR transcription is observed which may contribute to poor outcome from ischemia. A(1)AR overexpression selectively modifies post-ischemic gene expression, potentially contributing to ischemic-tolerance.
Ashton
Kevin J
KJ
Heart Foundation Research Centre, Griffith University Gold Coast Campus, Southport, Queensland, Australia.
Holmgren
Kirsty
K
Peart
Jason
J
Lankford
Amy R
AR
Paul Matherne
G
G
Grimmond
Sean
S
Headrick
John P
JP
D000818:Animals; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D005796:Genes; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017202:Myocardial Ischemia / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D015425:Myocardial Reperfusion; D020411:Oligonucleotide Array Sequence Analysis; D009924:Organ Culture Techniques; D010641:Phenotype; D016133:Polymerase Chain Reaction / Q000379:methods; D018047:Receptors, Purinergic P1 / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics; D015533:Transcriptional Activation
D018076:DNA, Complementary; D018047:Receptors, Purinergic P1