Transient receptor potential melastatin 4 contributes to early-stage endothelial injury induced by arsenic trioxide

Yu, Chenggang; Zhang, Yuyao; Wu, Xiayang; Tang, Hong; Liang, Ximing; Xue, Zhou-Ming; Xue, Yadong; Li, Jing; Zhu, Hui; Hu, Rong; Ban, Takahiko

doi:10.1016/j.toxlet.2019.04.035

Cited by 15 publications

(9 citation statements)

References 36 publications

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“…Our results confirmed that As 2 O 3 can induce HUVEC cells to undergo apoptosis, while crocetin can effectively rescue the As 2 O 3 -induced HUVEC programmed cell death (Figure 2B). In this study, As 2 O 3 -induced apoptosis was not as severe as that in Yu's experiments, where 5 μM As 2 O 3 induced about 40% apoptosis (31). Our results are consistent with those of Ma's findings, which showed that 5 μM As 2 O 3 was able to induce about 20% in vivo 35: 3157-3163 (2021) apoptosis in HUVEC cells (32).…”

Section: Discussionsupporting

confidence: 91%

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

Tsai

Chang

et al. 2021

In Vivo

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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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Section: Discussionsupporting

confidence: 91%

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

Tsai

Chang

et al. 2021

In Vivo

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“…For instance, TRPM4-mediated depolarization sustains LPS-induced cell death in HUVECs [ 302 ]. Likewise, TRPM4 sustains endothelial injury caused by arsenic trioxide (ATO) [ 303 ], a first-line chemotherapeutic drug that can induce severe cardiotoxicity and has, therefore, been discontinued [ 304 ]. A recent investigation showed that ATO-induced oxidative stress enhanced TRPM4 expression in HUVECs, which exacerbated TRPM4-mediated depolarization and Na + entry, resulted in cytosolic Ca 2+ overload, and promoted endothelial cell death [ 303 ].…”

Section: Therapeutic Applications and Pathological Implications Of Ros-induced Endothelial Ca 2+ Signalsmentioning

confidence: 99%

“…Likewise, TRPM4 sustains endothelial injury caused by arsenic trioxide (ATO) [ 303 ], a first-line chemotherapeutic drug that can induce severe cardiotoxicity and has, therefore, been discontinued [ 304 ]. A recent investigation showed that ATO-induced oxidative stress enhanced TRPM4 expression in HUVECs, which exacerbated TRPM4-mediated depolarization and Na + entry, resulted in cytosolic Ca 2+ overload, and promoted endothelial cell death [ 303 ]. It has long been known that excessive Na + entry through TRP channel drives reversal of NCX, thereby triggering a massive elevation in [Ca 2+ ] i in vascular endothelial cells [ 16 , 174 , 305 ].…”

Section: Therapeutic Applications and Pathological Implications Of Ros-induced Endothelial Ca 2+ Signalsmentioning

confidence: 99%

Reactive Oxygen Species and Endothelial Ca2+ Signaling: Brothers in Arms or Partners in Crime?

Negri¹,

Faris²,

Moccia³

2021

IJMS

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An increase in intracellular Ca2+ concentration ([Ca2+]i) controls virtually all endothelial cell functions and is, therefore, crucial to maintain cardiovascular homeostasis. An aberrant elevation in endothelial can indeed lead to severe cardiovascular disorders. Likewise, moderate amounts of reactive oxygen species (ROS) induce intracellular Ca2+ signals to regulate vascular functions, while excessive ROS production may exploit dysregulated Ca2+ dynamics to induce endothelial injury. Herein, we survey how ROS induce endothelial Ca2+ signals to regulate vascular functions and, vice versa, how aberrant ROS generation may exploit the Ca2+ handling machinery to promote endothelial dysfunction. ROS elicit endothelial Ca2+ signals by regulating inositol-1,4,5-trisphosphate receptors, sarco-endoplasmic reticulum Ca2+-ATPase 2B, two-pore channels, store-operated Ca2+ entry (SOCE), and multiple isoforms of transient receptor potential (TRP) channels. ROS-induced endothelial Ca2+ signals regulate endothelial permeability, angiogenesis, and generation of vasorelaxing mediators and can be exploited to induce therapeutic angiogenesis, rescue neurovascular coupling, and induce cancer regression. However, an increase in endothelial [Ca2+]i induced by aberrant ROS formation may result in endothelial dysfunction, inflammatory diseases, metabolic disorders, and pulmonary artery hypertension. This information could pave the way to design alternative treatments to interfere with the life-threatening interconnection between endothelial ROS and Ca2+ signaling under multiple pathological conditions.

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“…Then, cells were stained by TUNEL reaction solution for 1 h according to the manufacturer's instructions. 26 Later, cells were incubated with DAPI buffer for 10 min. Stained cell images were captured using a fluorescence microscope.…”

Section: Cell Membrane Integrity Testmentioning

confidence: 99%

HBCD, TBECH, and BTBPE exhibit cytotoxic effects in human vascular endothelial cells by regulating mitochondria function and ROS production

Shi

Wang

Chen

et al. 2021

Environmental Toxicology

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Brominated flame retardants (BFRs), such as, 1,2,5,6-tetrabromocyclooctane (HBCD), 1,2-dibromo-4-(1,2-dibromopropyl)cyclohexane (TBECH), and 1 1,2-bis-(2,4,6-tribromophenoxy)ethane (BTBPE), have garnered increasing attention due to their potent biological effects. In the present study, the toxicity of HBCD, TBECH, and BTBPE in human vascular endothelial cells (ECs) was explored. The data showed that HBCD, TBECH, and BTBPE induced cytotoxicity, namely dose-dependent cell viability reduction, cell membrane permeability and apoptosis increase, migration, and lumen formation inhibition. Moreover, HBCD was found to be more toxic than BTBPE or TBECH. Exposure to HBCD, TBECH, and BTBPE led to the production of reactive oxygen species, mitochondrial superoxide generation, and mitochondrial membrane potential collapse, implying that reactive stress caused the cytotoxicity.The ATP content, glutathione content, superoxide dismutase, and MDA activities were reduced, indicating that mitochondrial dysfunction may be the key mechanisms responsible for apoptosis. The present study suggested that mitochondria are a new target of BFRs in ECs and further deepened our understanding of the developmental toxicity of BFRs.

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Transient receptor potential melastatin 4 contributes to early-stage endothelial injury induced by arsenic trioxide

Cited by 15 publications

References 36 publications

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

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

Reactive Oxygen Species and Endothelial Ca2+ Signaling: Brothers in Arms or Partners in Crime?

HBCD, TBECH, and BTBPE exhibit cytotoxic effects in human vascular endothelial cells by regulating mitochondria function and ROS production

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