Exogenous Growth Differentiation Factor 15 (GDF15) exerts direct cardioprotective properties towards myocardial ischemia reperfusion injury

Abstract

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Agence National de la Recherche (ANR) Introduction 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 risk factor in several high cardiovascular risks situations such as myocardial infarction and coronary artery disease, experimental studies rather consider this cytokine as a cardioprotective molecule. Objective We therefore 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. Method In vivo ischemia reperfusion: Wistar male rats (200-340 g) were anesthetized with isoflurane and intubated before a left thoracotomy was performed between the 3rd and the 4th intercostal space. Rats were injected with either saline (Control groups) or 2.5 µg/kg of GDF15 (GDF15 groups), 20 minutes before the transient ligation of the left anterior descending artery for 30 min followed by 24h of reperfusion. Ex vivo ischemia reperfusion: Wistar male rats (250-400 g) were anesthetized with isoflurane before their hearts were isolated and perfused in a Langendorff model. Hearts were perfused either with saline (Control groups) or 2,000 ng/L of GDF15 upstream the coronary bed (GDF15 groups) for 10 minutes, then subjected to either 20 or 30 minutes of global normothermic total ischemia, followed by 2 h of reperfusion. Results GDF15 decreased the infarct size in vivo (42.4 ± 6 % vs. 65.3 ± 4.5 %, p<0.01) as well as in ex vivo (45.6 ± 3.8 % vs. 60.8 ± 3.8 %, p<0.05). Moreover, in our ex vivo model, GDF15 induced a better recovery of most contractile parameters after ischemia (higher left ventricular developed pressure, better heart rate recovery, better recovery in left ventricular contractility and relaxation, p<0.05 for all parameters). Conclusion These results demonstrate for the first time that exogenous preischemic short-term administration of GDF15 decreased cardiac cell death in vivo and also ex vivo, a situation where inflammatory, endocrine and nervous systems are not interfering. These original results suggest that GDF15 exerts direct cardioprotective properties towards ischemia-reperfusion injury. The molecular mechanisms have now to be investigated.