Abstract
Growth differentiation factor 15 (GDF15) is a stress-responsive cytokine, which can be produced under certain pathological situations, mainly related to inflammatory stress, aging and disease. While clinical data suggest that GDF15 is a powerful prognosis factor in several high-risk cardiovascular situations, experimental studies rather consider this cytokine as a cardioprotective molecule. We aimed to clarify the direct cardiac effects of GDF15 during ischemia-reperfusion (I-R) injury, at concentrations found in patients with high cardiovascular risk, such as these of patients presenting with acute myocardial infarction or stroke. Wistar male rats (200–400 g) were used for both in vivo and ex vivo ischemia-reperfusion and anesthetized with isoflurane. In vivo rats were injected with either saline (Control groups) or 2.5 μg/kg of GDF15 (GDF15 groups), 20 minutes before ischemia in the preconditioning protocol, or at the end of ischemia in the post-conditioning protocol. Myocardial ischemia was induced by the transient ligation of the left anterior descending artery for 30 min followed by 24 h of reperfusion. In a second set of experiments, rat's hearts were isolated and perfused ex vivo on a Langendorff model with either saline (Control groups) or 2000 ng/L of GDF15 upstream the coronary bed (GDF15 groups) for 10 minutes before ischemia or during reperfusion following 30 minutes of global normothermic total ischemia. GDF15 decreased the infarct size in vivo as well as in ex vivo when administrated before ischemia but not at the end of it. Moreover, in our ex vivo model, only GDF15 preconditioning induced a better recovery of most contractile parameters after ischemia (P < 0.05 for all parameters). These results demonstrate that exogenous GDF15 preconditioning decreased cardiac cell death in vivo but also ex vivo, the latter situation involving that inflammatory, endocrine, and nervous systems are not interfering. Suggesting that GDF15 exerts direct cardioprotective properties towards ischemia-reperfusion injury.
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