Arsenic trioxide induces growth inhibition and death in human pulmonary artery smooth muscle cells accompanied by mitochondrial increase and GSH depletion

Abstract

Arsenic trioxide (ATO; As O ) induces cell death in various cells via oxidative stress. Expose to chronic arsenic is involved in the development of vascular diseases. However, little is known about the cytotoxic effects of ATO on human normal vascular smooth muscle cells (VSMCs). Thus, in this study, we investigated the effects of ATO on cell growth and death in human pulmonary artery smooth muscle (HPASM) cells in relation to reactive oxygen species (ROS) and glutathione (GSH) levels. ATO treatment decreased the growth of HPASM cells with an IC of ∼30-50 μM at 24 h, and ATO induced HPASM cell death via apoptosis or necrosis dependent on the doses of it at this time. Treatment with 50 μM ATO did not increase ROS levels at the early time points, but it significantly increased mitochondrial O2•- levels at 24 h. ATO also induced GSH depletion in HPASM cells. N-acetyl cysteine (NAC; a well-known antioxidant) did not significantly affect apoptotic cell death, ROS levels, or GSH depletion in ATO-treated HPASM cells. However, l-buthionine sulfoximine (BSO; an inhibitor of GSH synthesis) intensified mitochondrial O2•- levels in ATO-treated HPASM cells, and significantly increased cell death and GSH depletion in these cells as well. In summary, we provided the first evidence that ATO inhibited the growth of HPASM cells, and induced apoptotic and/or necrotic cell death in these cells, accompanied by increases in mitochondrial O2•- level and GSH depletion.

Upregulation of thioredoxin and its reductase attenuates arsenic trioxide‑induced growth suppression in human pulmonary artery smooth muscle cells by reducing oxidative stress

“…ATO increases the production of ROS in numerous cells including SMCs (27)(28)(29)36). Likewise, ATO increased O 2…”

“…•increase and GSH depletion (36). In addition, PX-12 and auranofin induce the death of lung cancer and mesothelioma cells through oxidative stress (16,19).…”

“…•increase and GSH depletion (36). In the present study, the roles of Trx1 and TrxR1 proteins in the regulation of cell growth, death, ROS, and GSH levels were investigated in ATO-treated HPASMCs, and the effects of PX-12 and auranofin on cell metabolism, ROS, and GSH levels in HPASMCs were examined.…”

“…•levels in the control HPASMCs at approximately 30-180 min. However, neither adenovirus decreased DCF (ROS) and DHE (O 2 GSH is a non-protein thiol antioxidant crucial for protecting cells from oxidative stress and has a significant effect on ATO-, PX-12-, and auranofin-induced apoptosis in various cells including HPASMCs (16)(17)(18)(19)(20)28,36,(55)(56)(57). ATO significantly increased GSH (CMF) levels at 5 min and then steadily reduced the levels at 180 min.…”

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“…Cellular toxicity of arsenic was also found to be inversely related to intracellular GSH levels and thus may be enhanced by GSH depletion 38 . Ascorbic acid is known to be a powerful reducing agent, which helps in activating several enzymes, and acts as an antioxidant for detoxifying toxic substances.…”