Research Paper
Subject Category: Cardiovascular and pulmonary pharmacology
British Journal of Pharmacology (2008) 154, 105–113; doi:10.1038/bjp.2008.81; published online 10 March 2008
Resveratrol protects against arsenic trioxide-induced cardiotoxicity in vitro and in vivo
X-Y Zhao1,2,3, G-Y Li1,3, Y Liu1, L-M Chai1, J-X Chen1, Y Zhang1, Z-M Du1, Y-J Lu1,2 and B-F Yang1,2
- 1Department of Pharmacology, Harbin Medical University, Harbin, PR China
- 2State-Province Key Laboratories of Biomedicine Pharmaceutics, Harbin Medical University, Harbin, PR China
Correspondence: Dr B-F Yang, Department of Pharmacology, Harbin Medical University, Baojian Road 157, Harbin, Heilongjiang 150081, PR China. E-mail: yangbf@ems.hrbmu.edu.cn
3These authors made equal contribution to this study.
Received 16 November 2007; Revised 27 December 2007; Accepted 31 January 2008; Published online 10 March 2008.
Abstract
Background and purpose
The clinical use of arsenic trioxide (As2O3), a potent antineoplastic agent, is limited by its severe cardiotoxic effects. QT interval prolongation and apoptosis have been implicated in the cardiotoxicity of As2O3. The present study was designed to evaluate the effects of resveratrol on As2O3-induced apoptosis and cardiac injury.
Experimental approach
In a mouse model of As2O3-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 As2O3-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 As2O3-treated mice; these changes were prevented by pretreatment with resveratrol. In As2O3-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. As2O3-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 As2O3-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 As2O3. These observations suggested that resveratrol has the potential to protect against cardiotoxicity in As2O3-exposed patients.
Keywords:
apoptosis, long QT syndrome, arsenic trioxide, resveratrol, cardioprotective activity, reactive oxygen species
Abbreviations:
AO/EB, acridine orange/ethidium bromide; As2O3, arsenic trioxide; CAT, catalase; GSH-PX, glutathione peroxidase; LDH, lactate dehydrogenase; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; ROS, reactive oxygen species; SOD, superoxide dismutase; TUNEL, TdT-mediated dUTP nick end labelling
