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Sibjotang Protects against Cardiac Hypertrophy In Vitro and In Vivo
Chan-Ok Son1, Mi-Hyeon Hong2, Hye-Yoom Kim2
1Department of Ophthalmology, Konkuk University School of Medicine, Gwangjin-gu, Seoul 05030, Republic of Korea.
Insights
Sibjotang (SJT) effectively treats cardiac hypertrophy and heart failure by inhibiting key signaling pathways. This Korean traditional medicine protects against cardiotoxicity and reduces hypertrophy markers in both cell and animal models.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Traditional Korean Medicine
Background:
- Cardiac hypertrophy is a significant risk factor for heart failure, often developing secondary to conditions like myocardial infarction and hypertension.
- Doxorubicin (DOX) and isoproterenol (ISO) are commonly used to induce cardiotoxicity and cardiac hypertrophy in experimental models.
- Sibjotang (SJT), a traditional Korean medicine, is known to influence fluid balance and blood pressure, suggesting potential cardioprotective effects.
Purpose of the Study:
- To investigate the efficacy of Sibjotang (SJT) in mitigating doxorubicin (DOX)-induced cardiotoxicity in H9c2 cells.
- To explore the underlying molecular mechanisms by which SJT exerts its cardioprotective effects.
- To evaluate the therapeutic potential of SJT in an in vivo model of isoproterenol (ISO)-induced cardiac hypertrophy.
Main Methods:
- In vitro studies involved treating H9c2 cells with DOX and varying concentrations of SJT.
- In vivo studies utilized isoproterenol (ISO)-induced cardiac hypertrophy in mice, with SJT administered daily.
- Key molecular markers of hypertrophy, apoptosis, and signaling pathways (ERK1/2, p38 MAPK, calcineurin/NFAT/GATA4) were assessed using immunofluorescence and protein level analysis.
Main Results:
- SJT significantly reduced DOX-induced H9c2 cell enlargement and suppressed cardiac hypertrophic markers (ANP, BNP) in a dose-dependent manner.
- SJT inhibited the activation of ERK1/2 and p38 MAPK signaling pathways and decreased the expression of GATA4, calcineurin, and NFAT.
- In vivo, SJT administration attenuated ISO-induced cardiac hypertrophy, evidenced by reduced left ventricle/body weight ratio and suppressed hypertrophy markers.
Conclusions:
- Sibjotang (SJT) demonstrates significant cardioprotective effects against both DOX-induced cardiotoxicity and ISO-induced cardiac hypertrophy.
- SJT functions by inhibiting the calcineurin/NFAT/GATA4 signaling pathway, thereby reducing cardiac hypertrophy and apoptosis.
- SJT holds potential as a therapeutic agent for preventing and treating cardiac hypertrophy and subsequent heart failure.
Abstract:
Cardiac hypertrophy is developed by various diseases such as myocardial infarction, valve diseases, hypertension, and aortic stenosis. Sibjotang (, Shizaotang, SJT), a classic formula in Korean traditional medicine, has been shown to modulate the equilibrium of body fluids and blood pressure. This research study sought to explore the impact and underlying process of Sibjotang on cardiotoxicity induced by DOX in H9c2 cells. In vitro, H9c2 cells were induced by DOX (1 μM) in the presence or absence of SJT (1-5 μg/mL) and incubated for 24 h. In vivo, SJT was administrated to isoproterenol (ISO)-induced cardiac hypertrophy mice (n = 8) at 100 mg/kg/day concentrations. Immunofluorescence staining revealed that SJT mitigated the enlargement of H9c2 cells caused by DOX in a dose-dependent way. Using SJT as a pretreatment notably suppressed the rise in cardiac hypertrophic marker levels induced by DOX. SJT inhibited the DOX-induced ERK1/2 and p38 MAPK signaling pathways. In addition, SJT significantly decreased the expression of the hypertrophy-associated transcription factor GATA binding factor 4 (GATA 4) induced by DOX. SJT also decreased hypertrophy-associated calcineurin and NFAT protein levels. Pretreatment with SJT significantly attenuated DOX-induced apoptosis-associated proteins such as Bax, caspase-3, and caspase-9 without affecting cell viability. In addition, the results of the in vivo study indicated that SJT significantly reduced the left ventricle/body weight ratio level. Administration of SJT reduced the expression of hypertrophy markers, such as ANP and BNP. These results suggest that SJT attenuates cardiac hypertrophy and heart failure induced by DOX or ISO through the inhibition of the calcineurin/NFAT/GATA4 pathway. Therefore, SJT may be a potential treatment for the prevention and treatment of cardiac hypertrophy that leads to heart failure.
