Key result
Ischemic preconditioning significantly reduced infarct size in both wild type and CD73-deficient mice, demonstrating that extracellular adenosine formation by CD73 is not essential for early phase cardioprotection.
Why the study?
Does genetic inactivation of CD73 affect infarct size reduction by ischemic preconditioning in mouse models of myocardial infarction?
Does genetic inactivation of CD73 affect infarct size reduction by ischemic preconditioning in mouse models of myocardial infarction?
Extracellular adenosine formation by CD73 is not an essential trigger for the cardioprotective effects of early phase ischemic preconditioning in mice.
Mouse data indicate CD73 is dispensable for early preconditioning; leaves open alternative triggers before any clinical consideration.
BACKGROUND: Adenosine is a powerful trigger for ischemic preconditioning (IPC). Myocardial ischemia induces intracellular and extracellular ATP degradation to adenosine, which then activates adenosine receptors and elicits cardioprotection. Conventionally extracellular adenosine formation by ecto-5'-nucleotidase (CD73) during ischemia was thought to be negligible compared to the massive intracellular production, but controversial reports in the past demand further evaluation. In this study we evaluated the relevance of ecto-5'-nucleotidase (CD73) for infarct size reduction by ischemic preconditioning in in vitro and in vivo mouse models of myocardial infarction, comparing CD73-/- and wild type (WT) mice. METHODS AND RESULTS: 3x5 minutes of IPC induced equal cardioprotection in isolated saline perfused hearts of wild type (WT) and CD73-/- mice, reducing control infarct sizes after 20 minutes of ischemia and 90 minutes of reperfusion from 46 ± 6.3% (WT) and 56.1 ± 7.6% (CD73-/-) to 26.8 ± 4.7% (WT) and 25.6 ± 4.7% (CD73-/-). Coronary venous adenosine levels measured after IPC stimuli by high-pressure liquid chromatography showed no differences between WT and CD73-/- hearts. Pharmacological preconditioning of WT hearts with adenosine, given at the measured venous concentration, was evenly cardioprotective as conventional IPC. In vivo, 4x5 minutes of IPC reduced control infarct sizes of 45.3 ± 8.9% (WT) and 40.5 ± 8% (CD73-/-) to 26.3 ± 8% (WT) and 22.6 ± 6.6% (CD73-/-) respectively, eliciting again equal cardioprotection. The extent of IPC-induced cardioprotection in male and female mice was identical. CONCLUSION: The infarct size limiting effects of IPC in the mouse heart in vitro and in vivo are not significantly affected by genetic inactivation of CD73. The ecto-5'-nucleotidase derived extracellular formation of adenosine does not contribute substantially to adenosine's well known cardioprotective effect in early phase ischemic preconditioning.
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Wolff et al. (2015) studied Myocardial Infarction. Ischemic preconditioning (IPC) vs. Control (no preconditioning) was evaluated on Infarct size as a percentage of the area at risk in vivo (CD73-/- mice) (reduction by 44.2%, p=<0.001). Ischemic preconditioning significantly reduced infarct size in both wild type and CD73-deficient mice, demonstrating that extracellular adenosine formation by CD73 is not essential for early phase cardioprotection.
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