Diabetes-mediated elevated ferroptosis of endothelial cells accelerates blood- spinal cord barrier disruption in spinal cord injury rat

Abstract

Diabetes significantly aggravates spinal cord injury (SCI). The pathological mechanisms underlying it were still unclear, particularly the role of diabetes on blood spinal cord barrier (BSCB) after SCI. Endothelial cells (ECs) are the important component of BSCB. Here, we built the type 1 diabetes (T1D) combined with SCI rat model and tried to elucidate the role of diabetes on ECs after SCI. We confirmed that SCI impairs the permeability of BSCB and then blocks the recovery of locomotor function of rat, more importantly, diabetes significantly exacerbates it. Diabetes obviously induced the elevated ferroptosis level of ECs in spinal cord after SCI. Ferrostatin-1(Fer-1, ferroptosis inhibitor) administration significantly suppressed the ferroptosis level of ECs, and subsequently reversed the adverse role of diabetes on BSCB permeability and locomotor function of SCI rat. Mechanistic studies further observed that diabetes significantly activates RAGE signaling in ECs and induces excessive oxidative stress with abundance of ROS and abnormal mitochondria function in vivo and in vitro. After SCI, Fer-1 treatment also ameliorated diabetes-induced excessive oxidative stress level of ECs in spinal cord. Additionally, the human umbilical vein endothelial cells (HUVECs) were co-treated with high glucose, high lipid and H2O2 to mimic diabetes combined with SCI condition. The role of hyperglycemia on ferroptosis of ECs were also verified in vitro. In summary, diabetes significantly triggered the ferroptosis level of ECs via inducing elevated oxidative stress, and thus aggravated BSCB destruction of SCI rat, suggesting that ferroptosis will be a key target for the treatment of diabetes combined with SCI.