SOCS2 alleviates traumatic brain injury-induced mitochondrial damage and parthanatos in endothelial cells by inhibiting the JAK2/STAT3 signaling pathway.

BACKGROUND: Traumatic brain injury (TBI) is an important cause of death and disability worldwide. Vascular endothelial cells (ECs) injury has been confirmed to be a risk factor for the development of severe sequelae of TBI, and suppressor of cytokine signaling 2 (SOCS2) regulates the fate of endothelial cells. Therefore, this study aimed to investigate the role of SOCS2 in EC injury after TBI and elucidate its potential molecular mechanisms. METHODS: A TBI rat model was induced via controlled cortical impact (CCI), and a TBI cell model was constructed by treating RBE4 cells with oxygen-glucose deprivation (OGD). RT‒qPCR and western blotting were used to detect key gene and protein expression levels; JC-1 staining was applied to measure the mitochondrial membrane potential; a lactate dehydrogenase (LDH) release assay was conducted to assess the cell death rate; flow cytometry was utilized to detect reactive oxygen species (ROS) levels; and a neutral comet assay was performed to evaluate DNA damage. Additionally, hematoxylin‒eosin (H&E) staining, syndecan-1 content measurement, and the Evans blue extravasation test were combined to comprehensively assess brain tissue pathology and blood‒brain barrier integrity. RESULTS: Our study revealed that in TBI rat brain tissues and OGD-treated RBE4 cells, the expression of the endothelial barrier-related proteins ZO-1 and Occludin decreased, whereas the levels of parthanatos-associated proteins (PARP1, PAR, and nuclear AIF), JAK2/STAT3 signaling pathway activation markers (p-JAK2/JAK2 and p-STAT3/STAT3), and the DNA damage marker γ-H2AX significantly increased. Additionally, both TBI rat brain tissues and OGD-treated RBE4 cells exhibited reduced mitochondrial membrane potential and elevated ROS levels, with OGD-induced RBE4 cells showing substantial DNA damage and cell death. Notably, the expression of SOCS2 was downregulated in both the TBI and OGD models, and SOCS2 overexpression markedly alleviated the aforementioned injuries induced by TBI or OGD, suggesting that SOCS2 might mitigate TBI-related endothelial cell damage by reducing mitochondrial impairment and parthanatos. Mechanistically, SOCS2 attenuated PARP1-mediated mitochondrial damage and parthanatos by promoting PARP1 ubiquitination, triggering its degradation, and inhibiting the activation of the JAK2/STAT3 signaling pathway, ultimately ameliorating TBI-induced endothelial cell injury. CONCLUSION: Our study revealed a novel regulatory role of SOCS2 in EC injury following TBI and elucidated its underlying mechanism. This discovery of the previously unknown role of the SOCS2-PARP1-JAK2/STAT3 regulatory axis in the TBI-related damage to ECs will provide new ideas for the development of neuroprotective strategies targeting SOCS2.