Exogenous growth differentiation factor 15 (GDF15) exerts direct cardioprotective properties towards myocardial ischemia reperfusion injury

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 risk factor in several high-risk cardiovascular situations such as myocardial infarction and coronary artery disease, 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 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 24 h of reperfusion. Ex vivo rat's hearts were isolated and perfused on a Langendorff model with either saline (Control groups) or 2000 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. GDF15 decreased the infarct size in vivo as well as in ex vivo. Moreover, in our ex vivo model, GDF15 induced a better recovery of most contractile parameters after ischemia ( P < 0.05 for all parameters). These results demonstrate for the first time that exogenous preischemic short-term administration of GDF15 decreased cardiac cell death in vivo but also ex vivo, the latter situation involving that inflammatory, endocrine, and nervous systems are not interfering. These original results suggest that GDF15 exerts direct cardioprotective properties towards ischemia-reperfusion injury.