Exogenous growth differentiation factor 15 (GDF-15) 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 cardiovascular risks situations such as myocardial infarction and coronary artery disease, experimental studies rather consider this cytokine as a cardioprotective molecule. 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. 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 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 induced a better recovery of most contractile parameters after 30 minutes of ischemia (higher left ventricular developed pressure, better heart rate recovery, better recovery in left ventricular contractility and relaxation, P < 0.05 for all parameters). Moreover, after an irreversible 30-minute duration of ischemia, GDF15 decreased infarct size (45.6 ± 3.8% vs. 60.8 ± 3.8%, P < 0.05). These preliminary results demonstrate for the first time in an ex vivo isolated heart model, that exogenous preischemic short-term administration of 2000 ng/L exerts cardioprotective properties towards ischemia reperfusion injury, improving recovery of functional parameters and decreasing cardiac cell death.