Ox-LDL Induces Neuron Apoptosis and Worsens Neurological Outcomes in aSAH via Fas/FADD Pathway

The aim of this study was to assess the role of Ox-LDL (oxidized low-density lipoprotein) in the clinical prognosis of patients with aneurysmal subarachnoid hemorrhage (aSAH) and to investigate the underlying mechanisms in a mouse model of aSAH. Plasma Ox-LDL levels were measured in 50 aSAH patients and in 20 control patients via ELISA. Analysis of the associations between Ox-LDL levels and neurological function was carried out 1 year after discharge. The effects of Ox-LDL on aSAH model behavior and neurological damage were studied via Nissl staining and brain assessments. qRT‒PCR, Western blotting, and FITC/PI Apoptosis detection were performed in an aSAH cell model to reveal the effects of Ox-LDL on neurons. Protein docking and Fas knockdown were used to explore the role of the Fas/FADD pathway in the Ox-LDL-induced exacerbation of neuron dysfunction. Among aSAH patients, those with lower Ox-LDL levels (1.755 ± 0.2107 mmol/L) had an mRS score ≤ 2 after one year, whereas those with higher Ox-LDL levels (2.532 ± 0.1860 mmol/L) had an mRS score > 2. Mice that were injected twice weekly with 0.2 ml of Ox-LDL, seven times, experienced increased neurological damage and neuronal Apoptosis, activating the Fas/FADD pathway, an effect that was mirrored in the 20 µg/ml Ox-LDL-treated cell model. Blocking Fas/FADD with 170 µg of C75 or siRNA inhibited the apoptotic phenotype both in vivo and in vitro. Ox-LDL promoted neuronal Apoptosis via Fas/FADD pathway after aSAH. The inhibition of Ox-LDL could serve as a therapeutic strategy to prevent neuronal damage after aSAH and improve prognostic outcomes.

Fas; Neuron apoptosis; Oxidized low-density lipoprotein; Protein‒protein interaction.