Synergistic Anti-Vascular Inflammatory Effects and Molecular Mechanisms of Combined Phytochemicals in Endothelial Cells and Mice
Chronic pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) play key roles in the development of endothelial dysfunction and therefore induce cardiovascular disease (CVD), the number one killer of Americans. Emerging evidence shows that phytochemicals, the secondary plant metabolites present in a large variety of foods, have the potential ability in reducing risk of CVD. The aims of this study are to investigate the synergistic anti-vascular inflammatory effects of combined phytochemicals and define the relevant molecular mechanisms. Pairwise combinations from more than a dozen of phytochemicals at different concentrations were tested by the TNF-α-induced monocytes adhesion to human EA.hy 926 endothelial cells assay to screen optimum combinations. Two combinations curcumin (1μM) and luteolin (0.5μM), curcumin (5μM) and resveratrol (5μM) were selected, and these two combinations synergistically inhibited TNF-α-induced monocytes adhesion to human EA.hy 926 endothelial cells while the individual chemicals did not have such effect at the selected concentrations. The CI value of curcumin plus luteolin is 0.60, curcumin plus resveratrol is 0.78 respectively. Consistently, two-week dietary intake of combined curcumin (500 mg/kg) and luteolin (500mg/kg), curcumin (500 mg/kg) and resveratrol (200mg/kg) in male C57BL/6 mice synergistically prevented TNF-α-stimulated adhesion of mouse monocytes to aortic endothelium. We also found that TNF-α enhanced protein expressions of vascular cell adhesion molecule 1 (VCAM-1), monocyte chemotactic protein-1 (MCP-1) were synergistically reduced by these two combination in human EA.hy 926 cells, mouse aorta and mouse plasma while the individual chemical did not have these inhibitory effects. Furthermore, these two combinations synergistically inhibited TNF-α-increased nuclear factor (NF)-κB nuclear translocation in EA.hy 926 cells, the same patterns of inhibitions on monocytes adhesion, VCAM-1 and MCP-1 protein levels. Therefore, combined curcumin and luteolin, curcumin and resveratrol at physiological concentrations synergistically inhibits TNF-α-induced monocytes adhesion to endothelial cells and expressions of MCP-1 and VCAM-1 via suppressing NF-κB translocation into nucleus both in vitro and ex vivo. These results suggest that dietary intake of a combination of curcumin and luteolin, curcumin and resveratrol or relevant foods having high content of these phytochemicals may be an effective, safe and convenient approach to prevent vascular inflammation and therefore prevent/treat vascular diseases in humans.
"Synergistic Anti-Vascular Inflammatory Effects and Molecular Mechanisms of Combined Phytochemicals in Endothelial Cells and Mice"
ETD Collection for Tennessee State University.