Eugenosedin‐A ameliorates hyperlipidemia‐induced vascular endothelial dysfunction via inhibition of α₁‐adrenoceptor/5‐HT activity and NADPH oxidase expression

Abstract

Eugenosedin-A (Eu-A) effects on vascular endothelial dysfunction and oxidative stress in a hyperlipidemic rat model were investigated. Rats were randomly divided into four groups: two control groups and two treatment groups. The control rats received a regular diet or high fat diet (HFD); the treatment rats fed received an HFD with 5 mg/kg Eu-A or atorvastatin for 10 weeks. No changes in serotonin levels were observed in the four groups; norepinephrine levels were enhanced in the HFD group which was attenuated by Eu-A and atorvastatin. In the HFD group, the vascular reactivity was increased by vasoconstrictors (5-nonyloxytryptamine, 5-HT, and phenylephrine) and decreased by an endothelium-dependent vasorelaxant, carbachol. Protein levels of α1-adrenergic receptors (not 5-HT1B/2A), reactive oxygen species (ROS) p47(phox), p67(phox), and gp91(phox), and oxidative damage markers 3-nitrotyrosine (3-NT) and 4-hydroxy-2-nonenal (4-HNE) were increased, but endothelial nitric oxide synthase (eNOS), P-eNOS and vasodilator-stimulated phosphoprotein phosphorylation (P-VASP) were decreased. Catalase and superoxide dismutase (SOD-1 and SOD-2) proteins were increased, but glutathione peroxidase (GPx) was decreased in the aorta. Eu-A and atorvastatin reduced vasoconstrictor-induced aortic contractions that might be related to 5-HT1B/2A and α1-adrenergic receptors inhibitory activities. Eu-A and atorvastatin improved eNOS/P-eNOS, P-VASP, GPx, and malondialdehyde (MDA) levels, and decreased ROS and oxidative damage markers. Taken together, we suggest that Eu-A can ameliorate hyperlipidemia-induced vascular endothelial dysfunction and oxidative dysregulation.

Role of NADPH Oxidase in Metabolic Disease‐Related Renal Injury: An Update

“…As with other metabolic factors, such as hyperglycemia and hHcys, oxidative stress is proved to contribute to the deleterious effects of hyperlipidemia on renal injury. In high-fat diet fed mice, the expression of NADPH oxidase subunits, including p47phox, Nox2, and p67phox, was significantly upregulated, and the inhibitor could ameliorate hyperlipidemia-induced endothelial dysfunction via inhibition of NADPH oxidase expression [82]. However, in the study of Scheuer et al, it is reported that xanthine oxidoreductase rather than NADPH oxidase mainly accounted for the generation of ROS in glomeruli and tubulointerstitium induced by hyperlipidemia [83].…”

Dysfunctional Endothelial Progenitor Cells in Cardiovascular Diseases

“…Experimental studies and clinical trials have shown that reduced numbers and impaired functional capacity of EPCs occurred in patients with hypercholesterolemia or in cell culture with ox-LDL, whereas high-density lipoprotein cholesterol could be atheroprotective by increasing EPC numbers. 61 In a hypercholesteremic murine model of atherosclerosis, Kinkade et al 60 have recently identified NOX as the primary source of ROS in atherosclerotic lesions. The production of ROS is significantly increased in patients with hyperlipidemia.…”

Eugenosedin‐A improves glucose metabolism and inhibits MAPKs expression in streptozotocin/nicotinamide‐induced diabetic rats

“…Eu‐A reduced obesity‐related hyperglycemia, hyperinsulinemia, hyperlipidemia [13], inflammation, and adhesion molecules [14–16]. Eu‐A also inhibited high‐fat diet (HFD)‐induced vascular and endothelial dysfunction and oxidative stress by attenuating α 1‐ adrenoceptor/5‐HT activity and NADPH oxidase [16]. Based on our findings, Eu‐A could be used to control the HFD‐induced metabolic syndrome, which is associated with an increased risk of developing T2DM.…”