Abstract 144: Role of Iron Metabolism on Outcomes after Cardiac Arrest and Resuscitation in Mice

Abstract

Introduction: Ischemia and reperfusion (I/R) induces hepcidin in neurons and macrophages. Hepcidin downregulates ferroportin, the only known iron exporter, thereby inhibiting iron efflux and increases iron in ferroportin rich cells while decreasing serum iron. Increased intracellular iron after I/R induces ferroptosis, a regulated cell death characterized by iron-dependent lipid peroxidation. We hypothesized that hepcidin-induced sequestration of iron in neurons and macrophages, both of which express ferroportin, worsens post-cardiac arrest (CA) brain injury. Methods: Levels of hepcidin, iron, and a lipid peroxidation product, malondialdehyde; and expression of HAMP that encodes hepcidin, transferrin receptor 1, and markers of ferroptosis, PTGS2 and CHAC1, were measured in naïve and post-CA wild-type (WT) mice. To examine the effects of hepcidin on CA outcomes, hepcidin-deficient and WT mice were subjected to potassium-induced 8 min of CA followed by cardiopulmonary resuscitation (CPR). To determine the role of increased intracellular iron after CA/CPR, we administered iron-dextran (300 mg/kg IP) or vehicle to WT mice 24h before CA. The effect of liproxstatin-1, a ferroptosis inhibitor, on cell viability was assessed in murine primary cortical neurons after oxygen-glucose deprivation/reperfusion (OGD/R) with iron-loading. Results: Post-CA WT mice exhibited increased systemic HAMP expression, intracellular iron in spleen, and ferroptosis in brain. Hepcidin deficiency that decreases intracellular iron improved survival and neurological function after CA/CPR, whereas pre-arrest iron-loading that increases intracellular iron worsened survival and neurological function after CA/CPR (Fig. 1). Liproxstatin-1 improved neuron viability after OGD/R with iron-loading. Conclusions: Our data suggest that inhibiting hepcidin improves post-CA neurological outcomes by reducing intracellular iron and ferroptosis-induced neuronal death.