Abstract
BackgroundAdenosine 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 Results3x5 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.ConclusionThe 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.
Highlights
Cardioprotective mechanisms have become a field of intensive research since the first discovery of ischemic preconditioning (IPC) by Murry et al [1]: Short repetitive periods of ischemia and reperfusion (I/R) before the onset of an infarct-inducing index ischemia were found to greatly alleviate the resulting infarct size in dogs
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
Ischemic preconditioning by 3x5 minutes of repetitive ischemia/reperfusion was able to reduce infarct size to 26.8 ± 4.7% (WT) and 25.6 ± 4.7% (CD73-/-), eliciting a substantial cardioprotection in both WT and CD73-/- hearts with an average infarct size reduction by 42% (WT) and 54% (CD73-/-) in comparison to the respective control groups (n = 7–8, p < 0.001, Fig 2)
Summary
Cardioprotective mechanisms have become a field of intensive research since the first discovery of ischemic preconditioning (IPC) by Murry et al [1]: Short repetitive periods of ischemia and reperfusion (I/R) before the onset of an infarct-inducing index ischemia were found to greatly alleviate the resulting infarct size in dogs. Several related mechanisms such as ischemic postconditioning [2] and remote ischemic preconditioning [3,4] have been discovered thereafter, but IPC is known to elicit the strongest cardioprotection [5] and could be triggered in all species tested, including humans [6]. 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
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