Acetaldehyde dehydrogenase 2 attenuates lipopolysaccharide -induced endothelial barrier damage by inhibiting mitochondrial fission in sepsis-associated encephalopathy

Sepsis-associated encephalopathy (SAE) is a common neurological complication of sepsis, and acetaldehyde dehydrogenase 2 (ALDH2) has been identified as a protective factor for endothelial cells against oxidative stress. In this study, we aimed to investigate the therapeutic potential of ALDH2 and its impact on mitochondrial dynamics using both mouse and brain microvascular endothelial cells (BMECs) injury models induced by lipopolysaccharide (LPS). Our findings demonstrated that ALDH2 attenuated LPS-induced brain endothelial barrier damage, as evidenced by reduced brain water content and Evans blue dye in mice, decreased transepithelial electrical resistance (TEER), and increased fluorescein isothiocyanate-dextran (FITC-Dextran) leakage in bEnd.3 cells. Furthermore, ALDH2 reduced the levels of Reactive Oxygen Species (ROS) and malondialdehyde (MDA), while enhancing the activities of superoxide dismutase (SOD) and catalase (CAT). ALDH2 also decreased 4-HNE content and restored mitochondrial membrane potential and ATP production, promoting a balanced mitochondrial fission and fusion. Notably, our use of the mitochondrial fission inhibitor Mdivi-1 confirmed that ALDH2 alleviated mitochondrial damage by inhibiting dynamin-related protein 1 (Drp1). Consequently, our findings suggest that the effects of ALDH2 on LPS-induced blood-brain barrier (BBB) damage and oxidative stress may alleviate SAE by inhibiting Drp1 to maintain mitochondrial homeostasis.

ALDH2; Endothelial barrier; LPS; Mdivi-1; Mitochondrial fission and fusion; Oxidative stress.