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Ginsenoside Rc inhibits diabetic cardiomyopathy by reducing lipotoxicity through the adiponectin and autophagy
Wen Han1, Zhihui Wang1, Huilin Guo1
1Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100193, China; State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Beijing, 100193, China; Key Laboratory of New Drug Discovery Based on Classic Chinese Medicine Prescription, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100193, China.
Insights
Ginsenoside Rc improves diabetic cardiomyopathy by regulating glucose/lipid metabolism and enhancing autophagy. This compound shows potential for preventing and treating diabetic heart complications.
Area of Science:
- Cardiovascular Research
- Metabolic Disorders
- Pharmacology
Background:
- Diabetic cardiomyopathy (DCM) is a serious complication of diabetes mellitus, leading to heart failure through myocardial fibrosis and dysfunction.
- Ginsenoside Rc (Rc) is known for its antidiabetic and cardiovascular benefits, but its efficacy in DCM requires investigation.
Purpose of the Study:
- To investigate the underlying mechanisms by which Ginsenoside Rc (Rc) exerts protective effects against diabetic cardiomyopathy (DCM).
Main Methods:
- Established DCM in db/db mice and a lipotoxicity model in H9c2 cells.
- Assessed metabolic and adipokine indicators, cardiac function (echocardiography, histology), mitochondrial function, and autophagy.
- Utilized lipid metabolomics, qRT-PCR, and Western blot to analyze molecular pathways.
Main Results:
- Rc improved glycemic control, lipid profiles, and reduced inflammation in diabetic mice.
- Rc protected H9c2 cells from lipotoxicity, enhanced mitochondrial function, and reduced oxidative stress.
- Rc promoted adiponectin (APN) secretion, activating the AdipoR1/APPL1/LKB1/AMPKα2 pathway and enhancing autophagy.
Conclusions:
- Ginsenoside Rc ameliorates DCM by correcting metabolic disturbances, reducing oxidative stress and inflammation, and restoring mitochondrial function.
- Rc's therapeutic potential lies in activating the APN/AdipoR1/AMPK pathway to promote autophagy and combat lipotoxicity.
Background:
Diabetic cardiomyopathy (DCM), a consequential cardiovascular complication of diabetes mellitus, drives progressive myocardial fibrosis and cardiac dysfunction, culminating in heart failure (HF). Ginsenoside Rc (Rc) has significant antidiabetic and cardiovascular protective properties, but its potential to improve DCM is unclear.
Purpose:
The aim of this study was to explore the mechanism of Rc against DCM.
Methods:
The DCM model was established in db/db mice to evaluate the effects of Rc on metabolic and adipokine indicators in serum, and echocardiography and histological examinations were used to detect cardiac function in the mice. A lipotoxicity model of H9c2 cells was established using PA to verify the protective effect of Rc on cardiomyocytes, reduce lipotoxicity and improve mitochondrial function. The effect of Rc on adiponectin (APN) was demonstrated in 3T3 - L1 cells. Lipid metabolomics was used to explore the possible pathways by which Rc improves DCM. Quantitative reverse transcription polymerase chain reaction (qRT‒PCR) and western blot (WB) were used to detect gene and protein expression in mouse hearts and H9c2 cells.
Results:
Rc reduced body weight, glycemia, dyslipidemia, and inflammatory mediator levels in db/db mice. It alleviated myocardial fibrosis and lipid accumulation and protected against lipotoxicity-induced damage in H9c2 cells. Furthermore, Rc enhanced mitochondrial function in lipotoxic H9c2 cells while suppressing reactive oxygen species (ROS) generation. Rc also reduced hepatic lipid accumulation in db/db mice while decreasing lipid droplet accumulation in 3T3-L1 cells. Critically, Rc elevated circulating APN levels in both db/db mice and 3T3-L1 cells, which increased the expression of APPL1, LKB1 and AdipoR1 in both the hearts of db/db mice and lipotoxicity-induced H9c2 cells. Lipid metabolomics analysis of db/db mouse serum and urine revealed that Rc primarily regulated autophagy-related pathways. Rc significantly increased the number of autophagic vesicles in H9c2 cells with lipotoxicity and promoted autophagy pathways in both the hearts of db/db mice and lipotoxic H9c2 cells. This increased AMPKα2 phosphorylation, Beclin1 expression and the LC3II/LC3I ratio while reducing p62 expression.
Conclusion:
Collectively, these data indicated that Rc could rectify glucose/lipid metabolic perturbations, attenuate oxidative stress and inflammation, and restore mitochondrial functionality. Rc promoted APN secretion and activated the AdipoR1/APPL1/LKB1/AMPKα2 signaling pathway, further enhancing autophagy, increasing the ratio of LC3II/LC3Ⅰ and the expression of Beclin1, and decreasing the expression of p62, which reduced lipotoxicity and demonstrated potential for preventing and treating DCM.
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