Abstract 17159: Methionine Sulfoxide Reductase a Inducer Acacetin Confers Remarkable Anti-oxidation Effects Through Nrf2 Pathway in Human Endothelial Cells

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Introduction: Methionine sulfoxide reductase A (MsrA) is an important intracellular oxidoreductase and has significant cellular protection against oxidative damage. Our previous study has demonstrated that the constructed MsrA is highly effective in anti-oxidation and anti-inflammation in cultured mouse peritoneal macrophages, and can decrease atherosclerotic progress in apoE-/- mice. The present study investigates whether the natural flavone, acacetin could induce intracellular MsrA expression and protect endothelial cells against oxidative stress.

Methods: Human umbilical vein endothelial cell line (EA.hy926 cell) was used as a cell model to determine the potential protection effects of acacetin against oxidized low density lipoprotein (ox-LDL)-induced oxidative injury with multiple biochemical and molecular biological techniques.

Results: Acacetin antagonized the cell viability reduction and reactive oxygen species (ROS) production (P<0.05, 221.8%±24.67% vs. 292.5%±30.43% in ox-LDL treated cells, n≥5) induced by ox-LDL. Acacetin increased MsrA and Nrf2 protein levels (P<0.05, 1.32±0.06 and 1.43±0.12 fold of control, n≥5) in a concentration- dependent manner, and reversed the decreased cellular CAT and SOD levels induced by ox-LDL. Interestingly, cells transfected with MsrA siRNA remarkably decreased both MsrA and Nrf2 expressions (P<0.01, 0.29±0.08 and 0.65±0.05 fold of control, n≥5). Silencing MsrA vanished antagonized effects of acacetin on ox-LDL induced ROS production and decreased CAT and SOD levels, which suggested that anti-oxidation effect of acacetin may mediate through increased MsrA and Nrf2 pathway in EA.hy926 cell. The results also suggested that MsrA may be involved in Nrf2 pathway.

Conclusions: In conclusion, we demonstrate for the first time that acacetin is a MsrA inducer and confers anti-oxidation injury induced by ox-LDL via increasing MsrA level and enhancing anti-oxidative stress Nrf2 pathway in human umbilical vein endothelial cell line. Acacetin may be an effective antioxidant for therapeutic atherosclerosis. Study upon the effects of acacetin on atherosclerosis is under way in apoE-/- mice.

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