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Cinobufagin induced myocardial cell toxicity in H9c2 cells via inhibiting histone methyltransferase SMYD1 expression
Huimin Wu1, Chen Wang1, Hong Zhang1
1Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, PR China.
Abstract:
Cardiotoxicity of traditional Chinese medicines (TCMs) is an important factor in pharmacogenetic cardiovascular diseases, which directly affects the clinical use of TCM. Recently, cinobufagin (CBG), the active substance of Toad venom, has shown as a potential anti-tumor natural product. However, its cardiotoxicity limits the clinical application and the intrinsic mechanism is unclear. Here, we found that CBG induced oxidative stress and cell apoptosis in rat cardiomyocytes (H9c2), which caused cardiomyocyte injury. SET and MYND domain containing 1 (SMYD1) is a histone methyltransferase containing a SET-MYND domain, which is specifically expressed only in cardiomyocytes and skeletal muscle cells. RNA-Seq analysis revealed that the expression of SMYD1 was significantly decreased in the CBG treated H9c2 cells. Overexpression of SMYD1 alleviated CBG-induced myocardial injury, while knockdown of SMYD1 did the opposite. To summary, our study indicated that CBG induced cell apoptosis and oxidative stress via suppressing the expression of SMYD1 and ultimately leaded to myocardial toxicity. This research revealed the side-effects of CBG in myocardial toxicity and provided mechanism basis in specific disease conditions for CBG therapy.
Insights
Cinobufagin (CBG) from toad venom causes heart damage by increasing oxidative stress and cell death. This cardiotoxicity is linked to decreased expression of the SMYD1 gene in heart cells.
Area of Science:
- Pharmacology
- Cardiovascular Research
- Molecular Biology
Background:
- Cardiotoxicity of Traditional Chinese Medicines (TCMs) is a significant concern in pharmacogenetic cardiovascular diseases.
- Cinobufagin (CBG), derived from toad venom, shows anti-tumor potential but its clinical use is limited by unclear cardiotoxicity mechanisms.
Purpose of the Study:
- To investigate the mechanism underlying cinobufagin (CBG)-induced cardiotoxicity.
- To explore the role of SET and MYND domain containing 1 (SMYD1) in CBG-induced myocardial injury.
Main Methods:
- Utilized rat cardiomyocytes (H9c2) to assess CBG effects.
- Employed RNA-sequencing (RNA-Seq) to analyze gene expression changes.
- Investigated the impact of SMYD1 overexpression and knockdown on CBG-induced cardiotoxicity.
Main Results:
- CBG induced oxidative stress and apoptosis in cardiomyocytes, leading to injury.
- CBG treatment significantly decreased the expression of SMYD1.
- Overexpression of SMYD1 protected against CBG-induced myocardial injury, while knockdown exacerbated it.
Conclusions:
- CBG induces myocardial toxicity by suppressing SMYD1 expression, leading to apoptosis and oxidative stress.
- This study elucidates the mechanism of CBG cardiotoxicity, providing a basis for its therapeutic application in specific conditions.
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