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

Abstract

OBJECTIVES:

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.

• Authors: Kevin J Ashton, Kirsty Holmgren, Jason Peart, Amy R Lankford, G Paul Matherne, Sean Grimmond, John P Headrick
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 57 Issue 3 Pg. 715-26 (Mar 2003) ISSN: 0008-6363 [Print] England
• PMID: 12618233 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• DNA, Complementary
• Receptors, Purinergic P1

Topics

• Animals
• DNA, Complementary (genetics)
• Female
• Gene Expression Regulation
• Genes
• Male
• Mice
• Mice, Transgenic
• Myocardial Ischemia (genetics, metabolism, physiopathology)
• Myocardial Reperfusion
• Oligonucleotide Array Sequence Analysis
• Organ Culture Techniques
• Phenotype
• Polymerase Chain Reaction (methods)
• Receptors, Purinergic P1 (metabolism, physiology)
• Signal Transduction (genetics)
• Transcriptional Activation