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

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.

SUBMITTER: Wang R

PROVIDER: S-EPMC6384753 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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

Wang Ruiying R Zhang Jingyi J Wang Shan S Wang Min M Ye Tianyuan T Du Yuyang Y Xie Xueheng X Ye Jingxue J Sun Guibo G Sun Xiaobo X

Molecules (Basel, Switzerland) 20190202 3

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 ( ...[more]

PMID: 30717322

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Project description:BACKGROUND AND PURPOSE: The clinical use of arsenic trioxide (As(2)O(3)), a potent antineoplastic agent, is limited by its severe cardiotoxic effects. QT interval prolongation and apoptosis have been implicated in the cardiotoxicity of As(2)O(3). The present study was designed to evaluate the effects of resveratrol on As(2)O(3)-induced apoptosis and cardiac injury. EXPERIMENTAL APPROACH: In a mouse model of As(2)O(3)-induced cardiomyopathy in vivo, QT intervals and plasma enzyme activities were measured; cardiac tissues were examined histologically and apoptosis assessed. In H9c2 cardiomyocyte cells, viability, apoptosis, generation of reactive oxygen species (ROS) and cellular calcium levels were measured. KEY RESULTS: In the mouse model, resveratrol reduced As(2)O(3)-induced QT interval prolongation and cardiomyocyte injury (apoptosis, myofibrillar loss and vacuolization). In addition, increased lactate dehydrogenase activity and decreased activities of glutathione peroxidase, catalase and superoxide dismutase were observed in the plasma of As(2)O(3)-treated mice; these changes were prevented by pretreatment with resveratrol. In As(2)O(3)-treated H9c2 cardiomyocytes, resveratrol significantly increased cardiomyocyte viability and attenuated cell apoptosis as measured by acridine orange/ethidium bromide staining, TdT-mediated dUTP nick end labelling assay and caspase-3 activity. As(2)O(3)-induced generation of ROS and intracellular calcium mobilization in H9c2 cells was also suppressed by pretreatment with resveratrol. CONCLUSIONS AND IMPLICATIONS: Our results showed that resveratrol significantly attenuated As(2)O(3)-induced QT prolongation, structural abnormalities and oxidative damage in the heart. In H9c2 cardiomyocytes, resveratrol also decreased apoptosis, production of ROS and intracellular calcium mobilization induced by treatment with As(2)O(3). These observations suggested that resveratrol has the potential to protect against cardiotoxicity in As(2)O(3)-exposed patients.

Dataset Information

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

Publications

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

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