Abstract
This study was designed to investigate the effect of U50,488H (a selective κ-opioid receptor agonist) on endothelial function impaired by hyperlipidemia and to determine the role of Akt-stimulated NO production in it. Hyperlipidemic model was established by feeding rats with a high-fat diet for 14 weeks. U50,488H and nor-BNI (a selective κ-opioid receptor antagonist) were administered intraperitoneally. In vitro, the involvement of the PI3K/Akt/eNOS pathway in the effect of U50,488H was studied using cultured endothelial cells subjected to artificial hyperlipidemia. Serum total cholesterol and low-density lipoprotein cholesterol concentrations dramatically increased after high-fat diet feeding. Administration of U50,488H significantly alleviated endothelial ultrastructural destruction and endothelium-dependent vasorelaxation impairment caused by hyperlipidemia. U50,488H also increased Akt/eNOS phosphorylation and serum/medium NO level both in vivo and in vitro. U50,488H increased eNOS activity and suppressed iNOS activity in vivo. The effects of U50,488H were abolished in vitro by siRNAs targeting κ-opioid receptor and Akt or PI3K/Akt/eNOS inhibitors. All effects of U50,488H were blocked by nor-BNI. These results demonstrate that κ-opioid receptor stimulation normalizes endothelial ultrastructure and function under hyperlipidemic condition. Its mechanism is related to the preservation of eNOS phosphorylation through activation of the PI3K/Akt signaling pathway and downregulation of iNOS expression/activity.
Highlights
The maintenance of vascular integrity requires numerous endothelium-derived substances, among which nitric oxide (NO) is the most potent vasodilator
In the present study we proved for the first time that preventive treatment with U50,488H showed a significant effect to ameliorate endothelial dysfunction in hyperlipidemia through activation of κ-opioid receptor (κ-OR) and the PI3K/Akt/endothelial NO synthase (eNOS) pathway
This conclusion is based on following observations: 1) Ultrastructure analysis proved that U50,488H has an endothelial protective effect from morphological aspect
Summary
The maintenance of vascular integrity requires numerous endothelium-derived substances, among which nitric oxide (NO) is the most potent vasodilator. NO dilates blood vessels, inhibits platelet aggregation and adhesion, and suppresses leukocyte infiltration. It inhibits proliferation of vascular smooth muscle cells and oxidation of LDL5. An approach that possesses functions of stimulating NO production and inhibiting ONOO− formation would provide the best protection against vascular endothelial dysfunction[6]. Our previous work demonstrated that κ-opioid receptor (κ-OR) stimulation with U50,488H directly dilates vessels in a NO-dependent manner[7]. It attenuates pulmonary arterial pressure in rats with hypoxic pulmonary hypertension and effectively protects pulmonary artery endothelium through preservation of eNOS activity and anti-apoptotic effect. The present study was designed to determine whether κ-OR stimulation with U50,488H protects endothelial function in hyperlipidemia and its underlying mechanisms
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