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Endothelial cell injury in vascular arterial walls is a hallmark of atherosclerosis. Pterostilbene (Pts) has been shown to have an anti-oxidative and anti-apoptotic effect in numerous diseases via regulation of intracellular metabolism. The purpose of this study was to investigate the protective effect and possible mechanism of Pts against endothelial cell apoptosis in an atherosclerotic rat model. An atherosclerotic rat model was established using a high-fat, high glucose and high cholesterol diet. The effects of Pts on apoptosis and oxidative stress injury were measured using atherosclerotic lesion analysis, western blot analysis, hematoxylin and eosin straining, TUNEL assay and immunohistochemistry. In vivo results in an atherosclerosis rat model showed that Pts administration decreased the inflammatory response. Pts administration attenuated atherogenesis, reduced aortic plaque size, reduced macrophage infiltration, and suppressed oxidative stress and apoptosis of vascular arterial walls. In vitro assays using cultured human endothelial cells showed that Pts administration decreased hydrogen peroxide-induced cytotoxicity, oxidative stress injury and apoptosis via nuclear factor erythroid 2-related factor 2 (Nrf2) activation in endothelial cells. Additionally, Pts administration increased the expression level of Nrf2 and 5′ adenosine monophosphate-activated protein kinase (AMPK), and the phosphorylation level of AMPK and decreased signal transducer and activator of transcription 3 (STAT3) expression in these cells. Furthermore, knockdown of Nrf2 prevented Pts-decrease oxidative stress injury and apoptosis. In conclusion, these data suggest that Pts can protect endothelial cells in the vascular arterial walls against atherosclerosis-induced injury through regulation of the Nrf2-mediated AMPK/STAT3 pathway. [ABSTRACT FROM AUTHOR]