P664The anti-cancer drug Artemisinin protects against myocardial ischaemia-reperfusion injury via the recruitment of PI3K-AKT-p70S6k cell survival pathway.

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Abstract

Introduction: Recent studies have emphasised an important role for Artemisinin as an effective and potent anticancer cancer drug, with significantly less adverse effects in comparison to traditional chemotherapeutic agents. Most of the widely used cancer treatments are limited in use due to their dose dependent cardiotoxicity. Artemisinin has been found to be cardioprotective against myocardial ischaemia-reperfusion (IR) injury and and the aim of this study was to determine whether this protection involves recruitment of the PI3K-AKT-p70S6k-BAD cell survival pathway.

Methods: Isolated perfused rat hearts were subjected to 35 minutes of ischaemia followed by 120 minutes of reperfusion where Artemisinin (10nM-100μM) was administered throughout reperfusion in the presence and absence of PI3K inhibitor Wortmannin (100nM) or mTOR inhibitor Rapamycin (100nM). Hearts underwent triphenyl-tetrazolium staining for infarct size assessment or were frozen for Western blot analysis. Isolated adult rat ventricular myocytes, treated with Artemisinin (EC20: 4.3μM) and Wortmannin (100nM) or Rapamycin (100nM) were assessed for myocyte viability or cleaved-caspase 3, p-BAD or p-P70S6K activity compared to Hypoxia-Reoxygenation (H/R) control.

Results: Artemisinin treatment (ART) (10nM-100μM) showed a reduction in infarct size in a dose dependent manner. At EC20: 4.3μM, Artemisinin showed cardioprotection (38±0.03% IR+ART vs 50±0.04% IR, p < 0.001). The infarct-sparing effects of Artemisinin were reversed by the co-administration of Wortmannin (W) or Rapamycin (R) (IR+ART+W = 44±1.47% (p<0.001) and IR+ART+R = 42±1.47 % (p< 0.05) vs 38±2.55% IR+ART). In isolated adult rat ventricular myocytes Artemisinin administered throughout reoxygenation showed improvement in myocyte viability and decreased cleaved-caspase 3 activity compared to H/R control. This cytoprotective effect was abolished by the co-administration of either Wortmannin or Rapamycin. Furthermore, Artemisinin administered during reoxygenation induced a significant increase in p-Akt, p70s6K and p-BAD compared to non-treated time matched controls that was abolished in the presence of their respective inhibitors.

Conclusion: This is the first study to show Artemisinin protects the isolated perfused heart and cardiac myocytes from IR injury through the recruitment of the PI3K/AKT/p70S6K cell survival pathway.

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