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Farrerol Alleviates Diabetic Cardiomyopathy by Regulating AMPK-Mediated Cardiac Lipid Metabolic Pathways in Type 2
Jia Tu1, Qiaoling Liu2, Huirong Sun3
1Department of Critical Care Medicine, Xianning Central Hospital, The First Affiliated Hospital of Hubei University of Science and Technology, Xianning, 437199, China.
Insights
Farrerol (FA) improves diabetic cardiomyopathy (DCM) by activating the AMPK pathway, reducing cardiac lipid accumulation and fibrosis in rats. This natural compound offers a potential therapeutic strategy for diabetic heart disease.
Area of Science:
- Cardiovascular Research
- Metabolic Disorders
- Pharmacology
Background:
- Diabetic cardiomyopathy (DCM) is a serious complication of diabetes, leading to cardiac dysfunction and remodeling.
- The specific role of Farrerol (FA), a natural compound, in treating DCM remains largely uninvestigated.
- Understanding FA's mechanism is crucial for developing novel therapeutic interventions for diabetic heart complications.
Purpose of the Study:
- To investigate the therapeutic effects of Farrerol (FA) on diabetic cardiomyopathy (DCM) in a rat model.
- To elucidate the underlying molecular mechanisms by which FA exerts its protective effects against DCM.
- To assess FA's impact on cardiac function, myocardial structure, and metabolic pathways in diabetic conditions.
Main Methods:
- Established a type 2 diabetes mellitus (T2DM) model in Sprague-Dawley rats using a high-fat diet and STZ injection.
- Administered FA and Dapagliflozin (positive control) orally for 8 weeks, monitoring physiological and biochemical parameters.
- Evaluated cardiac function, myocardial injury, fibrosis, lipid accumulation, cardiomyocyte hypertrophy, and AMPK pathway protein expression via various assays and Western blot analysis. An in vitro model using H9c2 cells was also employed.
Main Results:
- FA treatment significantly ameliorated diabetic symptoms, cardiac dysfunction, myocardial fibrosis, cardiomyocyte hypertrophy, and lipid accumulation in T2DM rats.
- FA enhanced AMPK phosphorylation and PPARα expression while down-regulating CD36, indicating improved cardiac lipid metabolism.
- In vitro studies confirmed FA's ability to inhibit lipid formation and activate the AMPK signaling pathway in lipotoxic cardiomyocytes.
Conclusions:
- Farrerol (FA) demonstrates significant therapeutic potential in ameliorating diabetic cardiomyopathy (DCM) in a preclinical setting.
- FA's protective effects are mediated through the activation of the AMP-activated protein kinase (AMPK) signaling pathway, enhancing cardiac lipid metabolism.
- FA represents a promising natural compound for improving cardiac dysfunction and fibrosis associated with diabetes.
Abstract:
Diabetic cardiomyopathy (DCM) is a prevalent complication of diabetes mellitus characterized by cardiac dysfunction and myocardial remodeling. Farrerol (FA), an active ingredient in Rhododendron with various pharmacological activities, has an unclear specific role in DCM. Therefore, this study aims to investigate the effects of FA on DCM rats and elucidate its mechanism. The type 2 diabetes mellitus (T2DM) model was induced in adult male Sprague-Dawley rats by administering a high-fat diet for 8 weeks along with STZ injection. Subsequent to successful modeling, FA and the positive drug Dapagliflozin (Dapa) were orally administered via gavage for an additional 8-week period. After administration, the rats' body weight, fasting blood glucose, fasting insulin, and blood lipid profiles were quantified. Cardiac function was assessed through evaluation of cardiac function parameters, histopathological examination and measurement of myocardial enzyme markers were conducted to assess myocardial injury and fibrosis, Oil red O staining was utilized to evaluate myocardial lipid accumulation, wheat germ agglutinin (WGA) staining was used for assessing cardiomyocyte hypertrophy, and Western blot analysis was used to detect the proteins expression level of AMP-activated protein kinase (AMPK) pathway. The rat cardiomyocyte H9c2 were induced with palmitic acid to establish an in vitro cell model of myocardial lipid toxicity. Subsequently, the cells were subjected to treatment with FA and AMPK inhibitor Compound C, followed by assessment of lipid formation and expression levels of proteins related to the AMPK signaling pathway. The findings demonstrated that both FA and Dapa exhibited efficacy in ameliorating diabetic symptoms, cardiac dysfunction, myocardial fibrosis, cardiomyocyte hypertrophy, and lipid accumulation in T2DM rats. Additionally, they were found to enhance AMPK phosphorylation and PPARα expression while down-regulating CD36. Similarly, FA was observed to inhibit lipid formation in H9c2 and activate the AMPK signaling pathway. However, the improved effect of FA on lipotoxic cardiomyocytes induced by palmitic acid was partially reversed by Compound C. Therefore, the activation of the AMPK signaling pathway by FA may enhance cardiac lipid metabolism, thereby improving cardiac dysfunction and myocardial fibrosis in DCM rats.
