FXR contributes to obstructive jaundice-induced vascular hyporeactivity in mesenteric arteries by reconstituting BKCa channels - 17/08/24
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Highlights |
• | FXR plays a key role in OJ-induced vascular hyporesponsiveness. |
• | Electrophysiological activity increases with activated FXR in ASMCs from MAs in OJ rats. |
• | The activation of FXR boosts MaxiK-β1 expression but not MaxiK-α in MA myocytes of OJ rats. |
Abstract |
Objective |
Vascular hyporeactivity increases with the incidence of obstructive jaundice (OJ). Evidence suggests that OJ activates the farnesoid X receptor (FXR) as well as the large-conductance Ca2+-activated K+ (BKCa or MaxiK) channel. This study was designed to explore the role of the FXR in vascular hyporesponsiveness induced by cholestasis.
Methods |
The OJ model rats were constructed by bile duct ligation (BDL) and treated with an FXR agonist or antagonist. Vasoconstriction of the mesenteric arteries (MAs) was assessed in vitro. Whole-cell patch clamp recordings were used to investigate BKCa channel function. Real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot were used to detect mRNA and protein levels.
Results |
A significant increase in vascular tone and responsiveness to norepinephrine (NE) was observed after the MaxiK channel blocker (IbTX) was administered. This effect was pronounced in BDL animals and can be mimicked by the FXR agonist GW4064 and inhibited by the FXR antagonist Z-guggulsterone (Z-Gu). GW4064 has a similar effect as cholestasis in promoting MaxiK currents in isolated arterial smooth muscle cells (ASMCs), while Z-Gu blunted this effect. The mRNA and protein expression of FXR and MaxiK-β1, but not MaxiK-α, were significantly increased in the BDL group in comparison to the sham. Furthermore, activation or inhibition of FXR promoted or inhibited the mRNA and protein expression of the MaxiK-β1 subunit, respectively.
Conclusion |
Activation of FXR enhances the capability of the MaxiK channel to regulate vascular tone and leads to vascular hyporesponsiveness in the MAs of BDL rats, which may be mediated by the nonparallel upregulation of MaxiK-α and MaxiK-β1 subunit expression.
Le texte complet de cet article est disponible en PDF.Keywords : FXR, obstructive jaundice, BKCa, vascular hyporesponsiveness
Plan
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