The Cardiotoxicity Induced by Arsenic Trioxide is Alleviated by Salvianolic Acid A via Maintaining Calcium Homeostasis and Inhibiting Endoplasmic Reticulum Stress.

Ruiying Wang,Guibo Sun,Tianyuan Ye,Xiaobo Sun,Jingyi Zhang,Yuyang Du,Min Wang,Xueheng Xie,Shan Wang,Jingxue Ye

doi:10.3390/molecules24030543

Abstract

Arsenic trioxide (ATO) has been verified as a breakthrough with respect to the management of acute promyelocytic leukemia (APL) in recent decades but associated with some serious adverse phenomena, particularly cardiac functional abnormalities. Salvianolic acid A (Sal A) is a major effective component in treating ATO-induced cardiotoxicity. Therefore, the objective of our study was to assess whether Sal A had protective effects by the regulation of calcium homeostasis and endoplasmic reticulum (ER) stress. For the in vivo study, BALB/c mice were treated with ATO and/or Sal A via daily tail vein injections for two weeks. For the in vitro study, we detected the effects of ATO and/or Sal A in real time using adult rat ventricular myocytes (ARVMs) and an IonOptix MyoCam system. Our results showed that Sal A pretreatment alleviated cardiac dysfunction and Ca2+ overload induced by ATO in vivo and vitro. Moreover, Sal A increased sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA) activity and expression, alleviated [Ca2+]ER depletion, and decreased ER stress-related protein expression. Sal A protects the heart from ATO-induced injury and its administration correlates with the modulation of SERCA, the recovery of Ca2+ homeostasis, and the down-regulation of ER stress-mediated apoptosis.

Highlights

Arsenic-containing compounds have been used as medicines to treat multiple diseases, including cancer, syphilis and malaria, for more than 2000 years [1]
The experiment evaluated the effect of Salvianolic acid A (Sal A) through an in vivo mouse model of arsenic trioxide (ATO)-induced
We found that ATO upregulated the expression of GRP78, JNK, C/EBP-homologous protein (CHOP) and caspase-12, which were endoplasmic reticulum (ER) stress- and apoptosis-related proteins, and that Sal A treatment significantly attenuated these increases

Summary

Introduction

Arsenic-containing compounds have been used as medicines to treat multiple diseases, including cancer, syphilis and malaria, for more than 2000 years [1]. These compounds were not used worldwide until the Food and Drug Administration (FDA) approved arsenic trioxide (ATO). Worldwide until the Food and Drug Administration (FDA) approved arsenic trioxide (ATO) for the for the treatment of relapsed and refractory acute promyelocytic leukemia (APL) [2,3]. The clinical application application of ATO is hampered by cardiac toxicity manifesting as QT interval prolongation, torsade of ATO is hampered by cardiac toxicity manifesting as QT interval prolongation, torsade de pointes de pointes (TdP) or even sudden cardiac death [4,5].

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Conclusion