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19(S)-Hydroxyeicosatetraenoic Acid Promotes Airway Smooth Muscle Relaxation and Decreases DNA Synthesis Through the
Dina H D Mostafa1,2,3, Shana Kahnamoui2,4, Benjamin Van Bastelaere2,4
1Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, Max Rady College of Medicine.
Background:
19-Hydroxyeicosatetranoic acid (19-HETE) is an oxylipin derived from arachidonic acid through the action of cytochrome P450. The S-enantiomer of 19-HETE (19(S)-HETE) has vasodilatory potential, acting through the prostacyclin receptor (IP). However, no research has explored whether 19(S)-HETE has the same relaxant potential in the airways and what intracellular signaling networks are leveraged.
Methods:
Relaxation of murine trachea and airway smooth muscle cells were measured following exposure to 19(S)-HETE by myography and traction force microscopy. cAMP was measured by ELISA and inhibitors for IP, protein kinase A (PKA), and exchange proteins directly activated by cAMP (EPAC1/2) were used to probe intracellular signaling networks. DNA synthesis was measured using EdU incorporation assay.
Findings:
Murine airways and ASM cells produce 19(S)-HETE. 19(S)-HETE promotes relaxation in a dose dependent manner and reduces DNA synthesis. Compared to isoproterenol, 19(S)-HETE is less potent but more efficacious, with a higher maximal relaxation. 19(S)-HETE stimulated the IP receptor, triggering the formation of cAMP and the activation of PKA and EPAC1/2 downstream. Inhibition of both PKA and EPAC1/2 blunted 19(S)-HETE induced relaxation, but only EPAC2 prevented 19(S)-HETE induced changes in myosin phosphorylation (pMLC2). Similarly, only inhibition of EPAC2 reversed the changes in DNA synthesis.
Interpretation:
19(S)-HETE promotes ASM relaxation, through a mechanism dependent on the activation of IP receptor and downstream signaling through PKA and EPAC. However, the downstream events that lead to relaxation by PKA and EPAC are not the same, suggesting that more than reductions in pMLC2 are important in the action of 19(S)-HETE induced relaxation.
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