Abstract
BackgroundObesity-related diabetes mellitus leads to increased myocardial uptake and oxidation of fatty acids, resulting in a form of cardiac dysfunction referred to as lipotoxic cardiomyopathy. We have shown previously that Astragalus polysaccharides (APS) administration was sufficient to improve the systemic metabolic disorder and cardiac dysfunction in diabetic models.Methodology/Principal FindingsTo investigate the precise role of APS therapy in the pathogenesis of myocardial lipotoxity in diabetes, db/db diabetic mice and myosin heavy chain (MHC)- peroxisome proliferator-activated receptor (PPAR) α mice were characterized and administrated with or without APS with C57 wide- type mice as normal control. APS treatment strikingly improved the myocyte triacylglyceride accumulation and cardiac dysfunction in both db/db mice and MHC-PPARα mice, with the normalization of energy metabolic derangements in both db/db diabetic hearts and MHC-PPARα hearts. Consistently, the activation of PPARα target genes involved in myocardial fatty acid uptake and oxidation in both db/db diabetic hearts and MHC-PPARα hearts was reciprocally repressed by APS administration, while PPARα-mediated suppression of genes involved in glucose utilization of both diabetic hearts and MHC-PPARα hearts was reversed by treatment with APS.ConclusionsWe conclude that APS therapy could prevent the development of diabetic cardiomyopathy through a mechanism mainly dependent on the cardiac PPARα-mediated regulatory pathways.
Highlights
Diabetes mellitus affects more than 180 million people around the world, and this number is anticipated to increase to 300 million by 2025, within which type 2 diabetes might account for 90–95% [1]
We conclude that Astragalus polysaccharides (APS) therapy could prevent the development of diabetic cardiomyopathy through a mechanism mainly dependent on the cardiac PPARa-mediated regulatory pathways
To determine the therapeutic effects of APS treatment on cardiac dysfunction in lipotoxic cardiomyopathy with or without diabetes, echocardiography was performed on both db/db mice and MHCPPARa mice with or without APS treatment
Summary
Diabetes mellitus affects more than 180 million people around the world, and this number is anticipated to increase to 300 million by 2025, within which type 2 diabetes might account for 90–95% [1]. The diabetic heart is characterized by reduced glucose metabolism and enhanced FA utilization [5]. Data from several diabetic animal models indicated that diabetic hearts had elevated rates of FA oxidation, ectopic fat deposition and subsequent lipid peroxidation by peroxisome proliferator-activated receptor (PPAR) a regulatory pathways, leading to lipotoxic cardiomyopathy, which resulted in ventricular dysfunction [6,7]. Metabolic modulation to repress lipid oxidation and sustain glucose use in myocardium appeared to prevent cardiac dysfunction in models of severe type 2 diabetes [8,9]. Obesity-related diabetes mellitus leads to increased myocardial uptake and oxidation of fatty acids, resulting in a form of cardiac dysfunction referred to as lipotoxic cardiomyopathy. We have shown previously that Astragalus polysaccharides (APS) administration was sufficient to improve the systemic metabolic disorder and cardiac dysfunction in diabetic models
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