Adipocyte fatty acid-binding protein exacerbates cerebral ischaemia injury by disrupting the blood–brain barrier

Boya Liao, Leiluo Geng, Fang Zhang, Lingling Shu, Ling Wei, Patrick K K Yeung, Karen S L Lam, Sookja K Chung, Junlei Chang, Paul M Vanhoutte, Aimin Xu, Kai Wang*, Ruby L C Hoo*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

57 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)3169-3180
Number of pages12
JournalEuropean Heart Journal
Volume41
Issue number33
DOIs
Publication statusPublished - 1 Sept 2020

User-Defined Keywords

  • A-FABP
  • Blood–brain barrier
  • Ischaemic stroke
  • JNK/c-Jun signalling
  • MMP-9

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