Abstract | BACKGROUND/AIMS: METHODS: A rat model of As2O3-induced QT prolongation was generated by intravenous injection with As2O3. Surface electrocardiogram (ECG) and hemodynamics were employed to assess the LQTs and cardiac function. Intracellular calcium concentration ([Ca(2+)]i) and mitochondrial membrane potential (Δψm) were measured by confocal microscopy, and cardiomyocytes apoptosis were assessed by TUNEL assay. Western blot was applied to determine protein levels. RESULTS: We found for the first time that treatment with Gen significantly reversed LQTs and dose-dependently improved As2O3-induced impairment of cardiac function. As2O3 elevated [Ca(2+)]i and Gen mitigated this effect. Meanwhile, Gen significantly reversed As2O3-mediated cardiomyocytes apoptosis. Furthermore, Gen dose-dependently inhibited the phosphorylated JNK and p38-MAPK (pp38-MAPK), and blocked Δψm collapse, and further decreased cleaved caspase-3. CONCLUSION: Gen protects against the adverse cardiac effects of As2O3 partly by mitigating cardiomyocytes apoptosis induced by As2O3 through attenuating intracellular calcium overload and downregulating protein expression of p-JNK and pp38-MAPK to ameliorate the damage of Δψm leading to suppression of caspase-3 activation. Gen might be used as an adjunction therapy in APL patients receiving As2O3 treatment to avoid, at least to minimize, the adverse cardiac effects of As2O3.
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Authors | Yuhua Fan, Chen Wang, Yong Zhang, Pengzhou Hang, Yan Liu, Zhenwei Pan, Ning Wang, Zhimin Du |
Journal | Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
(Cell Physiol Biochem)
Vol. 31
Issue 1
Pg. 80-91
( 2013)
ISSN: 1421-9778 [Electronic] Germany |
PMID | 23363563
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2013 S. Karger AG, Basel. |
Chemical References |
- Anticarcinogenic Agents
- Arsenicals
- Calcium Channels, L-Type
- L-type calcium channel alpha(1C)
- Oxides
- Genistein
- JNK Mitogen-Activated Protein Kinases
- p38 Mitogen-Activated Protein Kinases
- Caspase 3
- Arsenic Trioxide
- Calcium
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Topics |
- Animals
- Anticarcinogenic Agents
(pharmacology, therapeutic use)
- Apoptosis
(drug effects)
- Arsenic Trioxide
- Arsenicals
- Calcium
(metabolism)
- Calcium Channels, L-Type
(genetics, metabolism)
- Caspase 3
(metabolism)
- Cells, Cultured
- Down-Regulation
- Electrocardiography
- Genistein
(pharmacology, therapeutic use)
- Hemodynamics
(drug effects)
- JNK Mitogen-Activated Protein Kinases
(metabolism)
- Long QT Syndrome
(chemically induced, drug therapy, physiopathology)
- Male
- Membrane Potential, Mitochondrial
(drug effects)
- Myocytes, Cardiac
(drug effects, metabolism)
- Oxides
(toxicity)
- Phosphorylation
- Rats
- Rats, Wistar
- p38 Mitogen-Activated Protein Kinases
(metabolism)
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