Evidence of transcriptional and translational components in anti-ischemic effects of adenosine

John P. Headrick*, Jason Peart, Kirsten Holmgren, Kevin Ashton

*Corresponding author for this work

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Abstract

Adenosine protects against myocardial ischemic injury via poorly defined mechanisms. We examined effects of inhibition of gene transcription, mRNA translation, and mitochondrial KATP channels on cardioprotective effects of adenosine in mouse hearts subjected to 20-min ischemia. Adenosine treatment reduced postischemic lactate dehydrogenase efflux (indicating necrosis) from 24 ± 2 to 9 ± 1 IU/g, and postischemic diastolic contracture from 21 ± 2 to 5 ± 2 mm Hg, and enhanced postischemic ventricular pressure development from 72 ± 3 to 135 ± 4 mm Hg. The antinecrotic response was reduced ≈50% by inhibition of protein translation (10 μM cycloheximide, CHX), unaltered by inhibition of transcription (20 μM actinomycin D, Act-D), and abrogated by mitochondrial KATP channel inhibition (100 μM 5-hydroxydecanoate, 5-HD). In contrast, protection against contractile dysfunction was reduced but not eliminated by CHX, Act-D, and 5-HD, and inhibitory effects CHX and Act-D were not additive with those of 5-HD, supporting a common mechanistic path. Inhibitory effects of Act-D were mimicked by 1.5 μM α-amanitin. These data provide evidence that adenosine limits necrosis in a mito KATP channel-dependent manner involving protein translation. The translational component is not dependent upon mRNA transcription. Adenosine also substantially reduces contractile dysfunction via a pathway involving mitochondrial KATP channel activation, protein translation, and mRNA transcription. Protection independent of this path was also evident. Thus, distinct signaling pathways appear to be involved in adenosine-mediated protection against postischemic necrosis and contractile dysfunction.

Original languageEnglish
Pages (from-to)454-460
Number of pages7
JournalDrug Development Research
Volume58
Issue number4
DOIs
Publication statusPublished - 1 Apr 2003
Externally publishedYes

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