Activation of retinoid receptor-mediated signaling ameliorates diabetes-induced cardiac dysfunction in Zucker diabetic rats
Autor: | Amar B. Singh, Irina Tsoy Nizamutdinova, Amin A. Mohammad, Jing Pan, Tatiana Souslova, Kenneth M. Baker, Jonathan A. Kendall, Rakeshwar S. Guleria |
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Rok vydání: | 2013 |
Předmět: |
Blood Glucose
Male medicine.medical_specialty Tetrahydronaphthalenes Diabetic Cardiomyopathies Receptors Retinoic Acid medicine.medical_treatment Drug Evaluation Preclinical Gene Expression Retinoid X receptor Biology Benzoates Article Insulin resistance Internal medicine Diabetic cardiomyopathy Diabetes mellitus medicine Animals Homeostasis Insulin Extracellular Signal-Regulated MAP Kinases Molecular Biology Protein kinase B Myocardium NF-kappa B Lipid metabolism Lipid Metabolism medicine.disease Rats Rats Zucker Oxidative Stress Glucose Retinoid X Receptors Endocrinology Diabetes Mellitus Type 2 Bexarotene Hypertrophy Left Ventricular Collagen Metabolic syndrome Cardiology and Cardiovascular Medicine Signal Transduction |
Zdroj: | Journal of Molecular and Cellular Cardiology. 57:106-118 |
ISSN: | 0022-2828 |
Popis: | Diabetic cardiomyopathy (DCM) is a significant contributor to the morbidity and mortality associated with diabetes and metabolic syndrome. Retinoids, through activation of retinoic acid receptor (RAR) and retinoid×receptor (RXR), have been linked to control of glucose and lipid homeostasis, with effects on obesity and diabetes. However, the functional role of RAR and RXR in the development of DCM remains unclear. Zucker diabetic fatty (ZDF) and lean rats were treated with Am580 (RARα agonist) or LGD1069 (RXR agonist) for 16 weeks, and cardiac function and metabolic alterations were determined. Hyperglycemia, hyperlipidemia and insulin resistance were observed in ZDF rats. Diabetic cardiomyopathy was characterized in ZDF rats by increased oxidative stress, apoptosis, fibrosis, inflammation, activation of MAP kinases and NF-κB signaling and diminished Akt phosphorylation, along with decreased glucose transport and increased cardiac lipid accumulation, and ultimately diastolic dysfunction. Am580 and LGD1069 attenuated diabetes-induced cardiac dysfunction and the pathological alterations, by improving glucose tolerance and insulin resistance; facilitating Akt activation and glucose utilization, and attenuating oxidative stress and interrelated MAP kinase and NF-κB signaling pathways. Am580 inhibited body weight gain, attenuated the increased cardiac fatty acid uptake, β-oxidation and lipid accumulation in the hearts of ZDF rats. However, LGD1069 promoted body weight gain, hyperlipidemia and cardiac lipid accumulation. In conclusion, our data suggest that activation of RAR and RXR may have therapeutic potential in the treatment of diabetic cardiomyopathy. However, further studies are necessary to clarify the role of RAR and RXR in the regulation of lipid metabolism and homeostasis. |
Databáze: | OpenAIRE |
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