Kansuinine A Ameliorates Atherosclerosis and Human Aortic Endothelial Cell Apoptosis by Inhibiting Reactive Oxygen Species Production and Suppressing IKKβ/IκBα/NF-κB Signaling

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.

Uric acid promotes myocardial infarction injury via activating pyrin domain-containing 3 inflammasome and reactive oxygen species/transient receptor potential melastatin 2/Ca2+pathway

“…It was reported that, high ROS production [ 29 ], TRPM2 channel currents [ 30 ], and calcium ion influx [ 31 ] could result in endothelial cell apoptosis and further accelerate MI. Therefore, the ROS production, TRPM2 channel currents, and calcium ion were measured after treatment with UA.…”

Mitochondrial dysfunction in vascular endothelial cells and its role in atherosclerosis

“…Pyroptosis is a programmed cell death characterized by plasma membrane rupture and followed by cellular contents and pro-inflammatory mediators release from rupture cell, playing a pro-atherosclerotic role ( Hoseini et al, 2018 ). EC mitochondrial ROS accumulation induced by trimethylamine N-oxide (TMAO) and low shear stress accelerate the formation of atherosclerotic plaques by inducing ECs pyroptosis in ApoE-deficient mice fed with a high-fat diet ( Chen C et al, 2021 ; Wu et al, 2020 ). TMAO is produced from the phosphatidylcholine metabolism of gut flora ( Schwartz and Reaven, 2012 ), which promotes succinate dehydrogenase complex subunit B (SDHB) upregulation in vascular EC ( Wu et al, 2020 ).…”

“…In addition to mentioned above, intracellular mtROS induce endothelial EndMT, senescence to promote atherosclerosis development ( Chen C et al, 2021 ; Jiang et al, 2020 ; L. Li L et al, 2021 ; N. Meng N et al, 2022 ; M. Zhu M et al, 2018 ).…”

Inflammation, Oxidative Stress, Senescence in Atherosclerosis: Thioredoxine-1 as an Emerging Therapeutic Target

“…Recently, Kansuinine A (KA), a natural product extracted from Euphorbia kansui , was reported as an inhibitor of H 2 O 2 -mediated upregulation of phosphorylated IKKβ, phosphorylated IκBα, and phosphorylated NF-κB. KA also reduced the Bax/Bcl-2 ratio and cleaved caspase-3 expression, preventing H 2 O 2 -induced vascular EC apoptosis, which is of great interest [ 229 ]. ROS-sensitive formulations have been widely used in atherosclerosis applications such as ROS scavenging, drug delivery, gene delivery, and imaging [ 230 ].…”