Abstract
Reactive oxygen species (ROS)-induced vascular endothelial cell apoptosis is strongly associated with atherosclerosis progression. Herein, we aimed to examine whether Kansuinine A (KA), extracted from Euphorbia kansui L., prevents atherosclerosis development in a mouse model and inhibits cell apoptosis through oxidative stress reduction. Atherosclerosis development was analyzed in apolipoprotein E-deficient (ApoE−/−) mice fed a high-fat diet (HFD) using Oil Red O staining and H&E staining. Human aortic endothelial cells (HAECs) were treated with KA, followed by hydrogen peroxide (H2O2), to investigate the KA-mediated inhibition of ROS-induced oxidative stress and cell apoptosis. Oil Red O staining and H&E staining showed that atherosclerotic lesion size was significantly smaller in the aortic arch of ApoE−/− mice in the HFD+KA group than that in the aortic arch of those in the HFD group. Further, KA (0.1–1.0 μM) blocked the H2O2-induced death of HAECs and ROS generation. The H2O2-mediated upregulation of phosphorylated IKKβ, phosphorylated IκBα, and phosphorylated NF-κB was suppressed by KA. KA also reduced the Bax/Bcl-2 ratio and cleaved caspase-3 expression, preventing H2O2-induced vascular endothelial cell apoptosis. Our results indicate that KA may protect against ROS-induced endothelial cell apoptosis and has considerable clinical potential in the prevention of atherosclerosis and cardiovascular diseases.
Highlights
Human aortic endothelial cells (HAECs) were pre-treated treated with BMS-345541 (IKK inhibitor, 25 μM) or BAY 11-7082 (NF-κB inhibitor, 1.0 μM), with BMS-345541 (IKK inhibitor, 25 μM) or BAY 11-7082 (NF-κB inhibitor, 1.0 μM), and we and we found that H2O2 caused a significant increase in Cleaved Caspase-3 (CC3) expression, which was comfound that H O caused a significant increase in CC3 expression, which was completely pletely reversed2 by2 BMS-345541 and BAY 11-7082 (n = 3; Figure 3B)
These findings sugreversed by BMS-345541 and BAY 11-7082 (n = 3; Figure 3B). These findings suggest gest that H2O2 significantly increased CC3 expression via the IKKβ/IκBα/NF-κB pathway that H2 O2 significantly increased CC3 expression via the IKKβ/IκBα/NF-κB pathway in in HAECs (Figure 3C), and this effect was reversed by Kansuinine A (KA)
Based on the screening platform, the findings of the present study indicate that KA protects HAECs from reactive oxygen species (ROS)-induced cellular damage
Summary
Cardiovascular diseases (CVDs), such as atherosclerosis-mediated myocardial infarction or stroke, are the leading cause of morbidity and mortality. These diseases are responsible for an estimated 17.9 million deaths each year, accounting for 31% of all deaths worldwide and placing a huge economic burden on health care systems globally [1,2]. The progression of CVDs is influenced by several factors, such as aging, hypertension, and atherosclerosis [3] These factors are associated with a long-term increase in oxidative stress, which causes vascular endothelial damage, due to the overproduction of reactive oxygen species (ROS) [4]. Large amounts of ROS lead to an increase in free radicals and lipid peroxides, which play a role in the pathogenesis of degenerative diseases, such as
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