Astragalus polysaccharides repress myocardial lipotoxicity in a PPARalpha-dependent manner in vitro and in vivo in mice

Background: The role of peroxisome proliferator-activated receptor alpha (PPAR alpha) in the development of myocardial lipotoxicity is widely observed in diabetic disorders. Thus, we investigated if treatment of Astragalus polysaccharides modulates lipotoxic cardiomyopathy both in vivo and in vitro through PPAR alpha mechanisms. Methodology/Principal Findings: The effects of Astragalus polysaccharides (APS) on PPAR alpha target gene expression and protein levels were tested in vitro and in vivo, including in mice with PPAR alpha cardiac-restricted overexpression [myosin heavy chain (MHC)-PPAR alpha] and in H9c2 embryonic rat cardiomyocytes with or without PPAR alpha agonist Echocardiographic studies, analyses of myocardial triglyceride and cardiac fuel utilization analyses were also performed in MHC-PPAR alpha mice. Treatment with APS prevented myocardial triglyceride accumulation and cardiac dysfunction in the MHC-PPAR alpha mice;with the normalization of energy metabolic derangements in hearts including reduced free fatty acids utilization and increased glucose uptake. Consistently, both in the MHC-PPAR alpha hearts and H9c2 cardiomyocytes with PPAR alpha agonist, the activation of PPAR alpha gene regulatory pathway involved in FFA-oxidation was down-regulated by APS treatment, while the suppression of PPAR alpha target genes involved in glucose uptake and oxidation was normalized by APS administration. Conclusions: Therapy with APS could prevent the development of lipotoxic cardiomyopathy through a mechanism mainly dependent on the cardiac PPAR alpha-mediated regulatory pathways. (C) 2015 Elsevier Inc. All rights reserved.