Protective Effects of Crocetin on Arsenic Trioxide-induced Oxidative Stress in Human Umbilical Vein Endothelial Cells

Abstract

Background/Aim: The clinical use of arsenic trioxide (As 2 O 3 ) is hampered due to its cardiotoxicity. Therefore, it is critical to prevent As 2 O 3 -induced loss of endothelial integrity. The purpose of this study was to examine As 2 O 3 -induced endothelial dysfunction and evaluate the efficacy of crocetin on reversing As 2 O 3 -induced cardiotoxicity. Materials and Methods: Cultured human umbilical vein endothelial cells (HUVECs) were used to examine As 2 O 3 -induced oxidative stress, apoptosis, production of reactive oxygen species (ROS) and DNA adducts. In addition, the impact of crocetin on As 2 O 3induced cardiotoxicity was evaluated. Results: As 2 O 3 decreased the viability of HUVEC cells and led to apoptosis. Additionally, As 2 O 3 elevated NADPH oxidase activity, and the levels of intracellular ROS. Furthermore, the formamidopyrimidine DNA-glycosylase-and endonuclease III-digestible adducts were induced by As 2 O 3 . Crocetin treatment reversed the As 2 O 3induced reduction in cell viability, the induction of apoptosis, the activation of NADPH oxidase activity, ROS levels and DNA adducts. Conclusion: Crocetin protects from As 2 O 3 -induced cardio-toxicity.Arsenic trioxide (As 2 O 3 ) is a very toxic agent used in Chinese medicine, which has been used to successfully treat refractory acute promyelocytic leukemia (1). The efficacy of As 2 O 3 has been reported for its capacity to induce acute promyelocytic leukemia cells to undergo apoptosis, however, its cardio-toxicity has hindered its therapeutic application (2, 3). In addition, accumulated literature has pointed that chronic exposure to As 2 O 3 from drinking water is closely associated with various human diseases, including atherosclerosis (4), diabetes mellitus (5), hypertension (6), ischemic heart disease (7, 8), peripheral vascular disease (9), and cancer (10,11). Up to date, relatively few published articles are available on the influence of acute or chronic As 2 O 3 exposure on the vascular endothelial system. At the same time, the identification of potential traditional Chinese medicine for the prevention of the diseases associated with chronic exposure to As 2 O 3 is of great interest. Εndothelial cells, human umbilical vein endothelial cells (HUVEC) are frequently used as the cell model, are the main targets of vasculopathy caused by As 2 O 3 exposure. As 2 O 3 has been reported to cause oxidative stress, and induce endothelial cells to undergo programmed cell death (12). Oxidative stress and its intracellular consequences are believed to be the major cause of As 2 O 3 cytotoxicity (13).Crocetin (C 20 H 24 O 4 ; molecular weight 328.4g/mol) is a primary constituent of saffron (Crocus sativus L), which has been known to possess lots of beneficial pharmacological effects, such as anti-inflammatory ( 14) and anti-apoptotic (15, 16). Crocetin has also been reported to effectively eliminate ischemia-reperfusion-induced oxidative damage in rats and scavenge free radicals (17). More interesting, crocetin has beneficial cardiovascular effects, su...

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