Abstract 10669: Activation of Retinoid Receptor-Mediated Signaling Ameliorates Diabetes-Induced Cardiac Dysfunction in Zucker Diabetic Fatty Rats
Retinoids, through the activation of retinoic acid receptor (RAR) and retinoid x receptor (RXR), regulate glucose and lipid homeostasis and protect cardiomyocytes from high glucose-induced apoptosis in vitro. However, the functional role of RAR and RXR in diabetic cardiomyopathy remains unclear. To determine the role of RAR and RXR in the regulation of metabolic and cardiac dysfunction in diabetic hearts, Zucker diabetic fatty (ZDF) and Zucker lean rats were divided into 6 groups (n=8) and treated with or without Am580 (RARα ligand) and LGD1069 (RXR ligand) for 16 weeks. The untreated ZDF rats showed hyperglycemia, hyperlipidemia, along with impaired cardiac Akt signaling, decreased cardiac gene expression of glucose transporter-1 (GLUT1) and GLUT4, aldolase A, hexokinase 2 and increased cardiac lipid deposition and gene expression of acetyl-coenzyme A acyltransferase 1 (Acaa1), Acaa2, acyl-coenzyme A dehydrogenase, carnitine palmitoyltransferase 1A and fatty acid binding protein 3. Cardiac hypertrophy, impaired systolic and diastolic heart function, fibrosis, inflammation and apoptosis were also observed in the hearts of untreated ZDF rats. Am580 improved cardiac dysfunction and inhibited the cardiac remodeling process, through decreasing insulin resistance and improving regulation of glucose and lipid metabolism in the heart of ZDF rats. Both Am580 and LGD1069 improved impaired insulin/Akt signaling, and inhibited the activation of JNK and NF-κB signaling. LGD1069 had similar beneficial effects on glucose metabolism and cardiac remodeling, as compared to Am580. However, LGD1069 had a distinct effect on lipid metabolism. Body weight, plasma triglycerides and cholesterol level were significantly increased in LGD1069 treated ZDF rats, along with increased cardiac lipid β oxidation and lipid deposition. In conclusion, chronic diabetes in ZDF rats resulted in cardiac dysfunction, along with cardiac glucose and lipid dysmetabolism. Activation of RAR and RXR-mediated signaling ameliorates heart dysfunction and cardiac remodeling, by improving insulin resistance and glucose metabolism. However, activation of RXR-mediated signaling further facilitates hyperlipidemia, obesity and cardiac lipid accumulation in diabetic animals.
- © 2012 by American Heart Association, Inc.