1. FABP4 a novel therapeutic target in ischaemic stroke
- Author
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Marco Bacigaluppi, Gianvito Martino, Bacigaluppi, M., and Martino, G.
- Subjects
medicine.medical_specialty ,A-FABP ,MEDLINE ,Fatty Acid-Binding Proteins ,Brain Ischemia ,Blood–brain barrier ,Text mining ,Basic Science ,Internal medicine ,Ischaemic stroke ,Adipocytes ,medicine ,Humans ,AcademicSubjects/MED00200 ,Ischemic Stroke ,business.industry ,JNK/c-Jun signalling ,Stroke ,Blood-Brain Barrier ,Ischemic stroke ,Thrombosis and Antithrombotic Therapy ,Cardiology ,lipids (amino acids, peptides, and proteins) ,MMP-9 ,Cardiology and Cardiovascular Medicine ,business - Abstract
Aims Adipocyte fatty acid-binding protein (A-FABP) is an adipokine implicating in various metabolic diseases. Elevated circulating levels of A-FABP correlate positively with poor prognosis in ischaemic stroke (IS) patients. No information is available concerning the role of A-FABP in the pathogenesis of IS. Experiments were designed to determine whether or not A-FABP mediates blood–brain barrier (BBB) disruption, and if so, to explore the molecular mechanisms underlying this deleterious effects. Methods and results Circulating A-FABP and its cerebral expression were increased in mice after middle cerebral artery occlusion. Genetic deletion and pharmacological inhibition of A-FABP alleviated cerebral ischaemia injury with reduced infarction volume, cerebral oedema, neurological deficits, and neuronal apoptosis; BBB disruption was attenuated and accompanied by reduced degradation of tight junction proteins and induction of matrix metalloproteinases-9 (MMP-9). In patients with acute IS, elevated circulating A-FABP levels positively correlated with those of MMP-9 and cerebral infarct volume. Mechanistically, ischaemia-induced elevation of A-FABP selectively in peripheral blood monocyte-derived macrophages and cerebral resident microglia promoted MMP-9 transactivation by potentiating JNK/c-Jun signalling, enhancing degradation of tight junction proteins and BBB leakage. The detrimental effects of A-FABP were prevented by pharmacological inhibition of MMP-9. Conclusion A-FABP is a key mediator of cerebral ischaemia injury promoting MMP-9-mediated BBB disruption. Inhibition of A-FABP is a potential strategy to improve IS outcome.
- Published
- 2020