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TongGuanWan Alleviates Doxorubicin- and Isoproterenol-Induced Cardiac Hypertrophy and Fibrosis by Modulating
Jung-Joo Yoon1, Ai-Lin Tai1,2, Hye-Yoom Kim1
1Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, 460, Iksan-daero, Iksan 54538, Republic of Korea.
Insights
TongGuanWan (TGW) effectively combats cardiac hypertrophy and fibrosis, common precursors to heart failure. This traditional herbal remedy demonstrated significant protective effects in both cell and animal models, suggesting its therapeutic potential.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Traditional Chinese Medicine
Background:
- Heart failure is a significant public health concern, often resulting from cardiac hypertrophy induced by stress or damage.
- Doxorubicin (DOX) and isoproterenol (ISO) are known inducers of cardiac hypertrophy via distinct mechanisms.
- Cardiac hypertrophy can progress to heart failure and other cardiovascular diseases.
Purpose of the Study:
- To investigate the therapeutic effects of TongGuanWan (TGW) on cardiac hypertrophy and fibrosis.
- To evaluate TGW's impact on cellular and molecular pathways involved in cardiac remodeling.
- To assess TGW's efficacy in both in vitro (DOX-induced H9c2 cells) and in vivo (ISO-induced mice) models.
Main Methods:
- Utilized DOX-induced H9c2 cell and ISO-induced mouse models to simulate cardiac hypertrophy and fibrosis.
- Assessed TGW's effects on cell surface area, cardiac biomarkers (ANP, BNP), and apoptosis-related factors (caspase-3, -9, Bax, Bcl-2).
- Investigated TGW's impact on key signaling pathways including MAPK, GATA-4/calcineurin/NFAT-3, and NF-κB, as well as fibrosis markers (fibronectin, α-SMA, collagen type I).
Main Results:
- TGW significantly reduced DOX-induced H9c2 cell enlargement and normalized cardiac biomarker levels.
- TGW inhibited the MAPK and GATA-4/calcineurin/NFAT-3 signaling pathways and reduced NF-κB translocation, mitigating inflammation.
- In vivo, TGW decreased heart and left ventricle weights, cardiac hypertrophy markers, and fibrosis in ISO-treated mice, with reduced fibronectin, α-SMA, and collagen type I.
Conclusions:
- TongGuanWan (TGW) exhibits significant cardioprotective effects against hypertrophy and fibrosis.
- TGW modulates key signaling pathways involved in cardiac remodeling, inflammation, and apoptosis.
- TGW demonstrates potential as a therapeutic agent for managing cardiac hypertrophy and fibrosis.
Abstract:
Heart failure, a major public health issue, often stems from prolonged stress or damage to the heart muscle, leading to cardiac hypertrophy. This can progress to heart failure and other cardiovascular problems. Doxorubicin (DOX), a common chemotherapy drug, and isoproterenol (ISO), a β-adrenergic agonist, both induce cardiac hypertrophy through different mechanisms. This study investigates TongGuanWan (TGW,), a traditional herbal remedy, for its effects on cardiac hypertrophy and fibrosis in DOX-induced H9c2 cells and ISO-induced mouse models. TGW was found to counteract DOX-induced increases in H9c2 cell surface area (n = 8, p < 0.01) and improve biomarkers like ANP (n = 3, p < 0.01)) and BNP (n = 3, p < 0.01). It inhibited the MAPK pathway (n = 4, p < 0.01) and GATA-4/calcineurin/NFAT-3 signaling, reduced inflammation by decreasing NF-κB p65 translocation, and enhanced apoptosis-related factors such as caspase-3 (n = 3, p < 0.01), caspase-9 (n = 3, p < 0.01), Bax (n = 3, p < 0.01), and Bcl-2 (n = 3, p < 0.01). Flow cytometry showed TGW reduced apoptotic cell populations. In vivo, TGW reduced heart (n = 8~10, p < 0.01), and left ventricle weights (n = 6~7), cardiac hypertrophy markers (n = 3, p < 0.01), and perivascular fibrosis in ISO-induced mice, with Western blot analysis confirming decreased levels of fibrosis-related factors like fibronectin, α-SMA (n = 3, p < 0.05), and collagen type I (n = 3, p < 0.05). These findings suggest TGW has potential as a therapeutic option for cardiac hypertrophy and fibrosis.
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