Arsenic trioxide induces the apoptosis in vascular smooth muscle cells via increasing intracellular calcium and ROS formation

Abstract

The present study was designed to investigate whether arsenic trioxide induced the apoptosis in rat mesenteric arterial smooth muscle cells (SMCs), which provides new insights into mechanisms of arsenic-related vascular diseases. Here, we found that arsenic trioxide significantly decreased the viability of SMCs in a dose-dependent manner. In addition, higher level of arsenic trioxide directly caused cellular necrosis. The Hoechst and AO/EB staining demonstrated that apoptotic morphological change was presented in SMCs exposed to arsenic trioxide. The TUNEL assay displayed that more positive apoptotic signal appeared in SMCs treated with arsenic trioxide. The following result showed that ROS formation was markedly increased in arsenic trioxide-treated SMCs. Pretreatment with N-acetylcysteine, an anti-oxidant reagent, obviously attenuated the enhancement of ROS production and the reduction of cell viability induced by arsenic trioxide in SMCs. Arsenic trioxide also enhanced free intracellular Ca(2+) level in SMCs. BAPTA also significantly prevented the increased intracellular Ca(2+) and decreased cell viability induced by arsenic trioxide in SMCs. These results suggested that arsenic trioxide obviously induced apoptosis in SMCs, and its mechanism was partially associated with intracellular ROS formation and free Ca(2+) increasing.

Arsenic induces apoptosis in myoblasts through a reactive oxygen species-induced endoplasmic reticulum stress and mitochondrial dysfunction pathway

“…It has been shown that lower concentrations of inorganic arsenic (0.02-0.5 lM) inhibit the myoblast differentiation (Steffens et al 2011;Yen et al 2010). Li et al (2010) reported that higher concentrations of As 2 O 3 (4-32 lM) obviously reduced smooth muscle cell viability in a concentration-dependent manner ). As 2 O 3 (3-10 lM) could also induce apoptosis in cultured bone marrow mesenchymal stem cells Yadav et al 2010).…”

“…Previous studies have demonstrated that low dose of inorganic arsenic is capable of inhibiting myoblast differentiation (Steffens et al 2011). Arsenic trioxide is known to be used to treat acute promyelocytic leukemia and can induce apoptosis in various cancer and normal cell lines Florea et al 2007;Li et al 2010;Lu et al 2011;Tang et al 2009). Intracellular reactive oxygen species (ROS) mediates multiple cellular responses, including protein kinase activation (Torres and Forman 2003), cell cycle progression (Boonstra and Post 2004), cell differentiation (Yen et al 2010), and apoptotic cell death (Orrenius et al 2007).…”

Synergistic antitumor activity of oridonin and arsenic trioxide on hepatocellular carcinoma cells

“…We found that oridonin, a diterpenoid isolated from traditional Chinese medicine Rabdosia rubescens, in combination with As 2 O 3 dramatically enhanced anti-tumor efficacy on human hepatoma cells in vitro and in vivo and this synergistic pro-apoptotic effect resulted from ROS mediated mitochondrial dysfunction and pro-survival signal inhibition. It is known that ROS is a critical mediator for As 2 O 3 induced apoptotic cell death (33), but treatment of Bel7402 cells with a relative low concentration of As 2 O 3 (8 µM) induced no detectable ROS production. Cancer cells seem to have higher level of endogenous oxidative stress compared with normal cells, and the upregulation of antioxidant capacity in adaptation to intrinsic oxidative stress can confer drug resistance (34).…”

Cardiovascular effects of arsenic: clinical and epidemiological findings

“…Moreover, As decreases in vitro vascular relaxation capability, both endothelium-dependent and endothelium-independent, directly acting on the smooth muscle cells (Lee et al 2003), while it potentiates response to vasoconstrictors through myosin light chain phosphorylation and Ca ++ sensitization/inflow (Lee et al 2005;Li et al 2010;Lim et al 2011). Interaction with arachidonic acid biotransformation, influencing vasoconstriction and relaxation, may be another mechanism (Bunderson et al 2004).…”