Deficiency of adipocyte fatty acid binding protein attenuates ischemia-induced cerebral injury via alleviating MMP-9 mediated blood-brain barrier disruption

Abstract

Ischemic stroke is a major disease leading to death and permanent disability worldwide. Adipocyte-fatty acid binding protein (A-FABP) is a lipid chaperone which is abundantly expressed in adipocyte and macrophage. Previous studies showed that A-FABP plays an important role in the regulation of inflammatory response and in the pathogenesis of metabolic diseases such as type 2 diabetes and atherosclerosis, which are the major risk factors of ischemic stroke. Increased circulating levels of A-FABP correlate positively with poor outcome in patients with ischemic stroke while no information is available concerning the pathogenesis role of A-FABP in the ischemic stroke. This study aims to investigate whether A-FABP exacerbates the outcome of ischemia cerebral injury, and if so, to explore the molecular mechanisms underlying this deleterious effect. To this end, eight-week-old A-FABP knockout (KO) mice and their WT littermates were subjected to transient middle cerebral artery occlusion (tMCAO). The outcome of ischemic stroke of those mice were evaluated. The therapeutic effect of the A-FABP selective inhibitor BMS309403 on ischemic stroke was evaluated. The molecular mechanisms on how A-FABP mediates detrimental effects on ischemic stroke were investigated by both ex vivo and in vitro studies. The clinical relevance of the serum level of A-FABP and infarct volume in patients with ischemic stroke were evaluated as well.

Key findings 1. Circulating A-FABP and its cerebral expression elevated in mice after middle cerebral artery occlusion (MCAO). 2. Genetic deletion and inhibition of A-FABP by selective inhibitor in mice alleviated cerebral ischemia injury with reduced infarction volume, cerebral edema, neurological deficits, and neuronal apoptosis; BBB disruption was attenuated and accompanied by decreased degradation of tight junction proteins and induction of matrix metalloproteinases-9 (MMP-9) 3. Mechanistically, ischemia-induced upregulation of A-FABP selectively in peripheral blood monocyte-derived macrophages and cerebral microglia promoted MMP-9 transactivation by potentiating JNK/c-Jun signaling, enhancing degradation of tight junction proteins and blood brain barrier (BBB) leakage. The detrimental effects of A-FABP were prevented by pharmacological inhibition of MMP-9. 4. Increased circulating A-FABP, was observed in patients within 24 hours of acute ischemic stroke onset, which was positively correlated with those of MMP-9 and cerebral infarct volume. These findings suggest A-FABP is a key mediator of ischemic stroke by promoting MMP-9 transactivation. A-FABP is a potential therapeutic target for ischemic stroke.