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Rhein alleviates diabetic cardiomyopathy by inhibiting mitochondrial dynamics disorder, apoptosis and hypertrophy in
Hejuan Li1, Genwang Wang2, Yi Tang3
1New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, China Pharmaceutical University, Nanjing, China.
Insights
Rhein, a rhubarb extract, shows promise in treating diabetic cardiomyopathy (DCM) by improving heart function and reducing cell damage. It protects against mitochondrial dysfunction, apoptosis, and hypertrophy, potentially by regulating ClpP levels.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Molecular Biology
Background:
- Diabetic cardiomyopathy (DCM) is a serious complication of diabetes with limited treatment options.
- Rhein, a natural compound from rhubarb, was investigated for its therapeutic potential in DCM.
Purpose of the Study:
- To evaluate the efficacy of Rhein in treating diabetic cardiomyopathy.
- To elucidate the underlying molecular mechanisms of Rhein's protective effects.
Main Methods:
- Utilized streptozotocin-induced DCM mouse models and high-glucose treated cardiomyocytes.
- Employed techniques including immunoblotting, qPCR, electron microscopy, echocardiography, and histopathology.
- Investigated the role of ClpP (a mitochondrial protease) in DCM and Rhein's effects.
Main Results:
- Rhein improved cardiac function, reduced myocardial fibrosis, and normalized cardiomyocyte size in DCM mice.
- Rhein ameliorated mitochondrial dynamics, decreased apoptosis, and inhibited cardiac hypertrophy markers.
- Rhein normalized elevated ClpP levels in DCM hearts; ClpP knockdown worsened cardiomyocyte injury.
Conclusions:
- Rhein demonstrates protective effects against diabetic cardiomyopathy.
- These benefits are attributed to improved mitochondrial dynamics, reduced apoptosis, and inhibited hypertrophy.
- Regulation of ClpP may be a key mechanism underlying Rhein's therapeutic action in DCM.
Background:
Diabetic cardiomyopathy (DCM) is a significant cardiovascular complication in diabetic patients, and treatment regimens are limited. Rhein, a compound extracted from the herb rhubarb, was investigated in this study for its efficacy on DCM and the potential mechanism.
Methods:
Streptozotocin-induced DCM mice, high-glucose (HG)-treated neonatal rat cardiomyocytes (NRCMs), and H9c2 cells with ClpP knockdown were used for the study. We performed phenotypic and molecular mechanistic studies using immunoblotting, quantitative polymerase chain reaction, transmission electron microscopy, cardiac echocardiography, and histopathological analysis.
Results:
Rhein improved the cardiac function and myocardial fibrosis, and decreased the cross-sectional area of cardiomyocytes in the DCM mice. It also improved mitochondrial dynamic disorder as evidenced by a decreased ratio of mitochondrial fission-related proteins p-Drp1S616/ Drp1 and increased expression of mitochondrial fusion proteins (Opa1, Mfn1 and Mfn2). Rhein mitigated apoptosis as indicated by decreased apoptosis-related proteins (caspase 9, cleaved-caspase 3 and Bax) and increased anti-apoptosis protein Bcl2 in the heart tissue of DCM mice. Upregulations of cardiac hypertrophy associated genes (ANP, BNP and β-MHC) were significantly inhibited by Rhein treatment. In addition, the level of ClpP, a mitochondrial protease, was increased in DCM, but was normalized by Rhein treatment. However, ClpP knockdown exacerbated cardiomyocyte injury in the presence or absence of HG in H9c2 cells, indicating that a normal level of ClpP is essential for cardiomyocytes to survive.
Conclusions:
Our results suggest that Rhein protects DCM by ameliorating mitochondrial dynamics disorder, inhibiting cardiomyocyte apoptosis, and myocardial hypertrophy. These protective effects of Rhein may be mediated by preventing ClpP upregulation.
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