Evodiamine Attenuates P2X(7)-Mediated Inflammatory Injury of Human Umbilical Vein Endothelial Cells Exposed to High Free Fatty Acids

Insulin resistance and type 2 diabetes mellitus (T2DM) are highly prevalent around the world. Elevated concentrations of free fatty acids (FFAs) are closely related to insulin resistance and T2DM. P2X(7) receptor is an ion channel gated by ATP, which is implicated in various scenarios including immune response, pain, and inflammation. In this study, we have explored whether P2X(7) receptor is involved in pathological changes in human umbilical vein endothelial cells (HUVECs) induced by high FFA treatment, and the potential beneficial effects of evodiamine. Evodiamine could effectively suppress the enhanced expression of P2X(7) receptor caused by high FFAs at both mRNA and protein levels. In addition, high FFA-induced cytotoxicity, the upregulated release of ATP, and production of reactive oxygen species (ROS) could be ameliorated by evodiamine in HUVECs. Evodiamine could also reverse the decreased NO formation and the increased adhesive events of immune cells at high FFAs. Moreover, evodiamine inhibited P2X(7)-dependent TNF-α expression and ERK 1/2 phosphorylation due to high FFAs. All these results indicated that evodiamine could correct the upregulated expression of P2X(7) receptor induced under high FFA condition in HUVECs, and consequently suppressed oxidative stress and inflammatory responses.