Therapy With Astragalus Polysaccharides Rescues Lipotoxic Cardiomyopathy In Mhc-Ppar Alpha Mice

Obesity-related diabetes mellitus leads to lipotoxic cardiomyopathy resulting in a form of cardiac dysfunction. Mice with heart-specific overexpression of peroxisome proliferator-activated receptor (PPAR) alpha showed a metabolic and cardiomyopathic phenotype similar to the diabetic heart. To define the role of Astragalus Polysaccharides (APS) treatment for PPAR alpha-mediated lipotoxicity in the pathogenesis of diabetic cardiomyopathy, myosin heavy chain [MHC]-PPAR alpha mice with high-fat diet were administrated with APS or vehicle for 16 weeks. The APS treatment prevented myocardial long-chain triglyceride accumulation, ultrastructure abnormality in cardiac myocytes and cardiac dysfunction in the MHC-PPAR alpha mice, which was associated with reduced free fatty acids (FFA) utilization and increased glucose uptake and oxidation in hearts by APS treatment. Consistent with the metabolic changes, activation of PPAR alpha gene regulatory pathway involved in FFA-oxidation in the MHC-PPAR alpha heart was down-regulated by APS treatment, while suppression of PPAR alpha target genes involved in glucose uptake and oxidation in the MHC-PPAR alpha hearts was normalized by APS administration. We conclude that therapy with APS might lead to the inhibition of PPAR alpha-mediate lipotoxicity in the pathogenesis of diabetic cardiomyopathy.