ABI3BP protects against cerebral ischemia-reperfusion injury by preserving blood-brain barrier integrity and activating PI3K/Akt signaling.

Blood-brain barrier (BBB) disruption represents acritical pathological featurein the pathogenesis of stroke. The extracellular matrix plays acritical rolein preserving the structural and functional integrity of the BBB. ABI3BP, an extracellular matrix protein, participatesin stem cell proliferation and differentiation, cellular senescence, tumor suppression, and extracellular matrix remodeling. However, the function and mechanism of ABI3BP in cerebral ischemia-reperfusion injury (IRI) remain unclear. In this study, we found that ABI3BP mRNA increased while protein expression decreased in the ischemic cortex, and serum ABI3BP level rose post-IRI. The thrombin inhibitor dabigatran reverses the reduction of ABI3BP after I/R injury. Thrombin hydrolyzed ABI3BP at arginine 337. Recombinant ABI3BP crossed the BBB, reduced infarct volume, improved neurological scores, restored blood flow, and decreased BBB leakage by upregulating ZO-1/Occludin in ischemic brain tissue. ABI3BP inhibits the expression of cleaved caspase-3 and increases the expression of Bcl-2/Bax, p-Akt/Akt, and p-PI3K/PI3K in vivo and in vitro. IRI induced the hydrolysis and decrease of endogenous ABI3BP level. Supplementation of recombinant ABI3BP protects against cerebral IRI by preserving BBB integrity, enhancing tight junction proteins, and suppressing endothelial apoptosis via PI3K/Akt signaling. Conclusively, these findings suggest that ABI3BP protects BBB integrity, potentially by restoring tight junction protein expression and inhibiting endothelial cell apoptosis after IRI, which suggests its promise as a therapeutic agent in ischemic stroke.