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Abstract
Soluble epoxide hydrolase (sEH) is a therapeutic target for cardiovascular diseases, including stroke. Current inhibitors act on the hydrolase catalytic site, but a human polymorphism (R287Q) reduces stroke risk despite being distant from this site, suggesting an alternative regulatory mechanism. Based on its location at the dimerization interface, we hypothesized that R287Q disrupts sEH dimerization, influencing enzymatic activity and localization. Using engineered mutations and a split-luciferase assay, we found that monomeric sEH exhibits reduced hydrolase activity compared to dimeric forms. GFP-tagged constructs revealed that dimer disruption increases peroxisomal localization in cortical neurons. In a mouse stroke model, sEH proteins capable of peroxisomal translocation conferred neuroprotection versus cytosolic-restricted variants. These findings indicate that dimerization regulates sEH activity and localization, and that targeting dimerization may represent a novel therapeutic strategy for ischemic brain injury.