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Activation of retinoid receptor-mediated signaling ameliorates diabetes-induced cardiac dysfunction in Zucker diabetic rats.

Abstract

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 x receptor (RXR), have been linked to control 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.

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  • Authors+Show Affiliations

    ,

    Division of Molecular Cardiology, Department of Medicine, College of Medicine, Texas A&M Health Science Center, Central Texas Veterans Health Care System, Temple, TX, USA.

    , , , , , ,

    Source

    MeSH

    Animals
    Benzoates
    Bexarotene
    Blood Glucose
    Collagen
    Diabetes Mellitus, Type 2
    Diabetic Cardiomyopathies
    Drug Evaluation, Preclinical
    Extracellular Signal-Regulated MAP Kinases
    Gene Expression
    Glucose
    Homeostasis
    Hypertrophy, Left Ventricular
    Insulin
    Lipid Metabolism
    Male
    Myocardium
    NF-kappa B
    Oxidative Stress
    Rats
    Rats, Zucker
    Receptors, Retinoic Acid
    Retinoid X Receptors
    Signal Transduction
    Tetrahydronaphthalenes

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    23395853

    Citation

    Guleria, Rakeshwar S., et al. "Activation of Retinoid Receptor-mediated Signaling Ameliorates Diabetes-induced Cardiac Dysfunction in Zucker Diabetic Rats." Journal of Molecular and Cellular Cardiology, vol. 57, 2013, pp. 106-18.
    Guleria RS, Singh AB, Nizamutdinova IT, et al. Activation of retinoid receptor-mediated signaling ameliorates diabetes-induced cardiac dysfunction in Zucker diabetic rats. J Mol Cell Cardiol. 2013;57:106-18.
    Guleria, R. S., Singh, A. B., Nizamutdinova, I. T., Souslova, T., Mohammad, A. A., Kendall, J. A., ... Pan, J. (2013). Activation of retinoid receptor-mediated signaling ameliorates diabetes-induced cardiac dysfunction in Zucker diabetic rats. Journal of Molecular and Cellular Cardiology, 57, pp. 106-18. doi:10.1016/j.yjmcc.2013.01.017.
    Guleria RS, et al. Activation of Retinoid Receptor-mediated Signaling Ameliorates Diabetes-induced Cardiac Dysfunction in Zucker Diabetic Rats. J Mol Cell Cardiol. 2013;57:106-18. PubMed PMID: 23395853.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Activation of retinoid receptor-mediated signaling ameliorates diabetes-induced cardiac dysfunction in Zucker diabetic rats. AU - Guleria,Rakeshwar S, AU - Singh,Amar B, AU - Nizamutdinova,Irina T, AU - Souslova,Tatiana, AU - Mohammad,Amin A, AU - Kendall,Jonathan A,Jr AU - Baker,Kenneth M, AU - Pan,Jing, Y1 - 2013/02/05/ PY - 2012/10/08/received PY - 2013/01/07/revised PY - 2013/01/29/accepted PY - 2013/2/12/entrez PY - 2013/2/12/pubmed PY - 2013/8/28/medline SP - 106 EP - 18 JF - Journal of molecular and cellular cardiology JO - J. Mol. Cell. Cardiol. VL - 57 N2 - 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 x receptor (RXR), have been linked to control 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. SN - 1095-8584 UR - https://www.unboundmedicine.com/medline/citation/23395853/Activation_of_retinoid_receptor_mediated_signaling_ameliorates_diabetes_induced_cardiac_dysfunction_in_Zucker_diabetic_rats_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022-2828(13)00055-2 DB - PRIME DP - Unbound Medicine ER -