Activation of Κ-Opioid Receptor Inhibits Inflammatory Response Induced by Sodium Palmitate in Human Umbilical Vein Endothelial Cells

Objectives: The current study aims to investigate the effect of kappa-opioid receptor (kappa-OR) activation on sodium palmitate (SP)-induced human umbilical vein endothelial cells (HUVECs) inflammatory response and elucidate the underlying mechanisms. Methods: A hyperlipidemic cell model was established and treated with kappa-OR agonist (U50,488H), and antagonist (norbinaltorphimine, nor-BNI), or inhibitors targeting PI3K, Akt or eNOS (LY294002, MK2206-2HCl or L-NAME, respectively). Furthermore, the expression levels of NLRP3, caspase-1, p-Akt, Akt, p-eNOS, and total eNOS were evaluated. Additionally, the production of reactive oxygen species, and levels of inflammatory factors, such as TNF-alpha, IL-1 beta, IL-6, IL-1 and adhesion molecules, such as ICAM-1, VCAM-1, P-selectin, and E-selectin were determined. The adherence rates of the neutrophils and monocytes were assessed as well. Results: The SP-induced hyperlipidemic cell model demonstrated increased expression of NLRP3 and caspase-1 proteins (P < 0.05) and elevated ROS levels (P < 0.01), and decreased phosphorylated-Akt and phosphorylated-eNOS expression (P < 0.05). In addition, SP significantly increased TNF-alpha, IL-1 beta, IL-6, ICAM-1, VCAM-1, P-selectin, and E-selectin levels (P < 0.01), decreased IL-10 levels (P < 0.01), and increased the adhesion rates of monocytes and neutrophils (P < 0.01). The SP-induced inflammatory response in HUVECs was ameliorated by kappa-OR agonist, U50,488H. However, the protective effect of U50,488H was abolished by kappa-OR antagonist, nor-BNI, and inhibitors of PI3K, Akt and eNOS. Conclusion: Our findings suggest that kappa-OR activation inhibits SP-induced inflammation by activating the PI3K/Akt/eNOS signaling pathway.