Arachidonic acid induces brain endothelial cell apoptosis via p38-MAPK and intracellular calcium signaling

Justin Evans, Yoo Seung Ko, Wilmer Mata, Muhammad Saquib, Joel Eldridge, Aaron Cohen-Gadol, H. Anne Leaver, Shukun Wang, Maria Teresa Rizzo

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Arachidonic acid (AA), a bioactive fatty acid whose levels increase during neuroinflammation, contributes to cerebral vascular damage and dysfunction. However, the mode of injury and underlying signaling mechanisms remain unknown. Challenge of primary human brain endothelial cells (HBECs) with AA activated a stress response resulting in caspase-3 activation, poly(ADP-ribose) polymerase cleavage, and disruption of monolayer integrity. AA also induced loss of mitochondrial membrane potential and cytochrome c release consistent with activation of intrinsic apoptosis. HBEC stimulation with AA resulted in sustained p38-MAPK activation and subsequent phosphorylation of mitogen-activated protein kinase activated protein-2 (MAPKAP-2) kinase and heat shock protein-27 (Hsp27). Conversely, other unsaturated and saturated fatty acids had no effect. Pharmacological and RNA interference-mediated p38α or p38β suppression abrogated AA signaling to caspase-3 and Hsp27, suggesting involvement of both p38 isoforms in AA-induced HBEC apoptosis. Hsp27 silencing also blocked caspase-3 activation. AA stimulated intracellular calcium release, which was attenuated by inositol 1,4,5-trisphosphate (IP3) receptor antagonists. Blockade of intracellular calcium release decreased caspase-3 activation, but had no effect on AA-induced p38-MAPK activation. However, inhibition of p38-MAPK or blockade of intracellular calcium mobilization abrogated AA-induced cytochrome c release. AA-induced caspase-3 activation was abrogated by pharmacological inhibition of lipooxygenases. These findings support a previously unrecognized signaling cooperation between p38-MAPK/MAPKAP-2/Hsp27 and intracellular calcium release in AA-induced HBEC apoptosis and suggest its relevance to neurological disorders associated with vascular inflammation.

Original languageEnglish (US)
Pages (from-to)145-158
Number of pages14
JournalMicrovascular Research
Volume98
DOIs
StatePublished - Mar 1 2015

Keywords

  • Apoptosis
  • Arachidonic Acid
  • Brain endothelial cells
  • Calcium
  • P38-MAPK

ASJC Scopus subject areas

  • Biochemistry
  • Cardiology and Cardiovascular Medicine
  • Cell Biology

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