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

Kevin J. Ashton, Kirsty Holmgren, Jason Peart, Amy R. Lankford, G. Paul Matherne, Sean Grimmond, John P. Headrick

Research output: Contribution to journalArticleResearchpeer-review

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Abstract

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.

Original languageEnglish
Pages (from-to)715-726
Number of pages12
JournalCardiovascular Research
Volume57
Issue number3
DOIs
Publication statusPublished - 1 Mar 2003
Externally publishedYes

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Adenosine A1 Receptors
Gene Expression
Ischemia
Genes
Reperfusion
Molecular Motor Proteins
Oligonucleotide Array Sequence Analysis
Real-Time Polymerase Chain Reaction
Molecular Biology
Proteins
Necrosis
Down-Regulation
Phenotype

Cite this

Ashton, K. J., Holmgren, K., Peart, J., Lankford, A. R., Matherne, G. P., Grimmond, S., & Headrick, J. P. (2003). Effects of A1 adenosine receptor overexpression on normoxic and post-ischemic gene expression. Cardiovascular Research, 57(3), 715-726. https://doi.org/10.1016/S0008-6363(02)00738-1
Ashton, Kevin J. ; Holmgren, Kirsty ; Peart, Jason ; Lankford, Amy R. ; Matherne, G. Paul ; Grimmond, Sean ; Headrick, John P. / Effects of A1 adenosine receptor overexpression on normoxic and post-ischemic gene expression. In: Cardiovascular Research. 2003 ; Vol. 57, No. 3. pp. 715-726.
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Ashton, KJ, Holmgren, K, Peart, J, Lankford, AR, Matherne, GP, Grimmond, S & Headrick, JP 2003, 'Effects of A1 adenosine receptor overexpression on normoxic and post-ischemic gene expression' Cardiovascular Research, vol. 57, no. 3, pp. 715-726. https://doi.org/10.1016/S0008-6363(02)00738-1

Effects of A1 adenosine receptor overexpression on normoxic and post-ischemic gene expression. / Ashton, Kevin J.; Holmgren, Kirsty; Peart, Jason; Lankford, Amy R.; Matherne, G. Paul; Grimmond, Sean; Headrick, John P.

In: Cardiovascular Research, Vol. 57, No. 3, 01.03.2003, p. 715-726.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Ashton, Kevin J.

AU - Holmgren, Kirsty

AU - Peart, Jason

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N2 - 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.

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