MAG-EPA and 17,18-EpETE target cytoplasmic signalling pathways to reduce short-term airway hyperresponsiveness.

Abstract

This study was aimed to investigate the role of eicosapentaenoic acid monoacylglyceride (MAG-EPA) and 17,18-epoxyeicosatetraenoic acid (17,18-EpETE) on the regulation of contractile reactivity and nuclear protein expression in 72-h-cultured and TNF-α-treated guinea pig tracheal rings. Tension measurements performed on native tissues demonstrated that the cytochrome P-450 epoxygenase (CYP450)-dependent EPA metabolite, 17,18-EpETE, displayed a higher potency than MAG-EPA in inhibiting U-46619-induced tone. Calphostin C (a PKC inhibitor), whether in association or not with MAG-EPA or 17,18-EpETE, had no further effect, while 17,18-EpETE and Y-27632 (a Rho kinase inhibitor) yielded additive effects. Of note, MAG-EPA and 17,18-EpETE pre-treatments normalized the contractile responses to broncho-constrictive agents in 72-h-cultured trachea. The enhanced expression of TNF-α, P-p65-nuclear factor kappaB (NF)-κB, c-fos and c-Jun in 72-h-cultured tissues likely contributed to the hyperresponsiveness. β-Escin-permeabilized preparations demonstrated that 17,18-EpETE abolished Ca(2+) hypersensitivity, suggesting a blunting of PKC and/or Rho kinase activation. Lastly, activation of NF-κB and activating protein-1 (AP-1) signalling by exogenous TNF-α markedly increased the contractile response to MCh, through an increase in 17-kDa PKC-potentiated inhibitory protein of PP1 (CPI-17) phosphorylation and IκBα degradation. Dual incubation of 17,18-EpETE with calphostin C or Y-27632 induced cumulative inhibitory effects on MCh responses in TNF-α-incubated tracheal rings. 17,18-EpETE also reduced the detection level of P-p65-NF-κB and AP-1 subunits. The present data provide evidence that MAG-EPA, through its bioactive metabolite, represents a prospective pharmacological target in respiratory diseases.

• Authors: Rayan Khaddaj-Mallat, Éric Rousseau
• Journal: Pflugers Archiv : European journal of physiology (Pflugers Arch) Vol. 467 Issue 7 Pg. 1591-1605 (Jul 2015) ISSN: 1432-2013 [Electronic] Germany
• PMID: 25113382 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 1-eicosapentaenoylglycerol
• Arachidonic Acids
• Bronchoconstrictor Agents
• Monoglycerides
• NF-kappa B
• Tumor Necrosis Factor-alpha
• 17,18-epoxy-5,8,11,14-eicosatetraenoic acid
• rho-Associated Kinases
• JNK Mitogen-Activated Protein Kinases
• Phosphoprotein Phosphatases
• Calcium

Topics

• Animals
• Arachidonic Acids (pharmacology)
• Bronchoconstriction
• Bronchoconstrictor Agents (pharmacology)
• Calcium (metabolism)
• Cytoplasm (metabolism)
• Female
• Guinea Pigs
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Male
• Monoglycerides (pharmacology)
• Muscle, Smooth (drug effects, metabolism, physiology)
• NF-kappa B (metabolism)
• Phosphoprotein Phosphatases (metabolism)
• Signal Transduction
• Trachea (drug effects, metabolism, physiology)
• Tumor Necrosis Factor-alpha (metabolism)
• rho-Associated Kinases (antagonists & inhibitors)