Eugenosedin-A prevents high-fat diet increased adhesion molecules through inhibition of MAPK- and p65-mediated NF-κB pathway in rat model

Abstract

Abstract Objectives Previous studies have shown eugenosedin-A, a 5-HT1B/2A and α1/α2/β1-adrenergic blocker, is able to decrease cholesterol levels, hyperglycaemia and inflammation in hyperlipidaemic mice induced by high-fat diet (HFD). The aim of this study is to examine the effects of eugenosedin-A on the inhibition of adhesion molecules of platelets, the aorta and acyl-coenzymeA:cholesterol acyltransferase-1 (ACAT-1) of macrophages in a hyperlipidaemic rat model. Methods Six-week-old Sprague–Dawley rats were randomly divided into two control and treatment groups. The control rats received either a regular diet or HFD and the treatment groups were fed HFD with either 5 mg/kg eugenosedin-A or atorvastatin for a 10-week period. Key findings Compared with the two control groups, the HFD group had lower levels of high-density lipoprotein, higher concentrations of triglycerides, total cholesterol, low-density lipoprotein and insulin. The expression of adhesion molecules in platelets, aorta and monocyte-macrophage were enhanced by HFD. HFD also increased upstream proteins and their phosphorylated form in the aorta. In treatment groups, eugenosedin-A and atorvastatin improved HFD-induced hyperlipidaemia and levels of insulin. Eugenosedin-A reduced the upregulation of P-selectin, ICAM-1, ICAM-2, ICAM-3, VCAM, PECAM in platelets and inhibited E-selectin, ICAM-1, ICAM-2, ICAM-3, VCAM and PECAM protein levels in the aorta. Eugenosedin-A reduced the ACAT-1 protein expression of monocyte-macrophages. The expression of PKCα, MAPKs, IKKα and p65 and their phosphorylated form were reduced in treatment groups. Conclusions Taken together, hyperlipidaemia enhances the expression of adhesion molecules and ACAT-1 protein, and eugenosedin-A ameliorates those increases. Through inhibition of MAPK- and p-65-mediated NF-κB pathway, eugenosedin-A decreases the quantity of adhesion molecules.