Arsenic trioxide triggered calcium homeostasis imbalance and induced endoplasmic reticulum stress-mediated apoptosis in adult rat ventricular myocytes. Issue 2 (18th February 2016)

• Record Type: Journal Article
• Authors: Zhang, Jing-yi; Sun, Gui-bo; Wang, Min; Liao, Ping; Du, Yu-yang; Yang, Ke; Sun, Xiao-bo
• Is Part Of: Toxicology research. Volume 5:Issue 2(2016:Mar.)
• Page Start: 682
• Page End: 688
• Publication Date: 2016-02-18
• Subjects: Toxicology -- Periodicals; 615.9005
• DOI: 10.1039/c5tx00463b
• Languages: English
• ISSNs: 2045-452X

Abstract

Abstract : Arsenic trioxide (ATO) is a potent anticancer drug agent but its clinical use is often limited by severe cardiotoxicity. Abstract : Arsenic trioxide (ATO) is a potent anticancer drug agent but its clinical use is often limited by severe cardiotoxicity. However, its exact mechanism remains poorly understood. In this study, we simultaneously explored the direct effect of ATO on cardiac contraction in adult rat ventricular myocytes and its effects on Ca 2+ transient in real time by using an IonOptix MyoCam system. The results showed that ATO increased the amplitude of sarcomere shortening, the maximal velocity of relengthening and shortening (−d L /d t max and +d L /d t max ), time-to-90% relengthening (TR90), and time-to-peak shortening (TPS), resulting in abnormal cardiomyocyte contraction. Meanwhile, ATO markedly increased the resting Ca 2+ ratio, amplitude/resting calcium, the maximal velocity of Ca 2+ shortening and relaxation (+d[Ca 2+ ]/d t max and −d[Ca 2+ ]/d t max ), time-to-50% peak [Ca 2+ ] i and the decay rate of [Ca 2+ ] i transients, suggesting that ATO leads to intracellular imbalance of calcium homeostasis. ATO also inhibited sarcoplasmic reticulum Ca 2+ -ATPase 2a (SERCA2a) activity in a time-dependent manner and activated the endoplasmic reticulum (ER) stress reaction. These results revealed that ATO dramatically aggravates Ca 2+ overload and promotes ER stress, eventually causing abnormal cardiomyocyte contraction in a dose-dependent and time-dependent manner.