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High glucose-induced repression of RAR/RXR in cardiomyocytes is mediated through oxidative stress/JNK signaling.

Abstract

The biological actions of retinoids are mediated by nuclear retinoic acid receptors (RARs) and retinoid X receptors (RXRs). We have recently reported that decreased expression of RARα and RXRα has an important role in high glucose (HG)-induced cardiomyocyte apoptosis. However, the regulatory mechanisms of HG effects on RARα and RXRα remain unclear. Using neonatal cardiomyocytes, we found that ligand-induced promoter activity of RAR and RXR was significantly suppressed by HG. HG promoted protein destabilization and serine-phosphorylation of RARα and RXRα. Proteasome inhibitor MG132 blocked the inhibitory effect of HG on RARα and RXRα. Inhibition of intracellular reactive oxidative species (ROS) abolished the HG effect. In contrast, H(2)O(2) stimulation suppressed the expression and ligand-induced promoter activity of RARα and RXRα. HG promoted phosphorylation of ERK1/2, JNK and p38 MAP kinases, which was abrogated by an ROS inhibitor. Inhibition of JNK, but not ERK and p38 activity, reversed HG effects on RARα and RXRα. Activation of JNK by over expressing MKK7 and MEKK1, resulted in significant downregulation of RARα and RXRα. Ligand-induced promoter activity of RARα and RXRα was also suppressed by overexpression of MEKK1. HG-induced cardiomyocyte apoptosis was potentiated by activation of JNK, and prevented by all-trans retinoic acid and inhibition of JNK. Silencing the expression of RARα and RXRα activated the JNK pathway. In conclusion, HG-induced oxidative stress and activation of the JNK pathway negatively regulated expression/activation of RAR and RXR. The impaired RAR/RXR signaling and oxidative stress/JNK pathway forms a vicious circle, which significantly contributes to hyperglycemia induced cardiomyocyte apoptosis.

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    ,

    Division of Molecular Cardiology, Department of Medicine, College of Medicine, Texas A&M Health Science Center, Central Texas Veterans Health Care System, Temple, Texas 76504, USA.

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    Source

    Journal of cellular physiology 227:6 2012 Jun pg 2632-44

    MeSH

    Alitretinoin
    Animals
    Animals, Newborn
    Apoptosis
    Cysteine Proteinase Inhibitors
    Dose-Response Relationship, Drug
    Glucose
    HEK293 Cells
    Humans
    Hyperglycemia
    JNK Mitogen-Activated Protein Kinases
    MAP Kinase Kinase 7
    MAP Kinase Kinase Kinase 1
    Mitogen-Activated Protein Kinase 1
    Mitogen-Activated Protein Kinase 3
    Myocytes, Cardiac
    Oxidants
    Oxidative Stress
    Phosphorylation
    Promoter Regions, Genetic
    Proteasome Endopeptidase Complex
    Proteasome Inhibitors
    Protein Kinase Inhibitors
    RNA Interference
    Rats
    Rats, Sprague-Dawley
    Receptors, Retinoic Acid
    Retinoic Acid Receptor alpha
    Retinoid X Receptor alpha
    Signal Transduction
    Time Factors
    Transcriptional Activation
    Transfection
    Tretinoin
    p38 Mitogen-Activated Protein Kinases

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural

    Language

    eng

    PubMed ID

    21882190

    Citation

    Singh, Amar B., et al. "High Glucose-induced Repression of RAR/RXR in Cardiomyocytes Is Mediated Through Oxidative stress/JNK Signaling." Journal of Cellular Physiology, vol. 227, no. 6, 2012, pp. 2632-44.
    Singh AB, Guleria RS, Nizamutdinova IT, et al. High glucose-induced repression of RAR/RXR in cardiomyocytes is mediated through oxidative stress/JNK signaling. J Cell Physiol. 2012;227(6):2632-44.
    Singh, A. B., Guleria, R. S., Nizamutdinova, I. T., Baker, K. M., & Pan, J. (2012). High glucose-induced repression of RAR/RXR in cardiomyocytes is mediated through oxidative stress/JNK signaling. Journal of Cellular Physiology, 227(6), pp. 2632-44. doi:10.1002/jcp.23005.
    Singh AB, et al. High Glucose-induced Repression of RAR/RXR in Cardiomyocytes Is Mediated Through Oxidative stress/JNK Signaling. J Cell Physiol. 2012;227(6):2632-44. PubMed PMID: 21882190.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - High glucose-induced repression of RAR/RXR in cardiomyocytes is mediated through oxidative stress/JNK signaling. AU - Singh,Amar B, AU - Guleria,Rakeshwar S, AU - Nizamutdinova,Irina T, AU - Baker,Kenneth M, AU - Pan,Jing, PY - 2011/9/2/entrez PY - 2011/9/2/pubmed PY - 2012/4/20/medline SP - 2632 EP - 44 JF - Journal of cellular physiology JO - J. Cell. Physiol. VL - 227 IS - 6 N2 - The biological actions of retinoids are mediated by nuclear retinoic acid receptors (RARs) and retinoid X receptors (RXRs). We have recently reported that decreased expression of RARα and RXRα has an important role in high glucose (HG)-induced cardiomyocyte apoptosis. However, the regulatory mechanisms of HG effects on RARα and RXRα remain unclear. Using neonatal cardiomyocytes, we found that ligand-induced promoter activity of RAR and RXR was significantly suppressed by HG. HG promoted protein destabilization and serine-phosphorylation of RARα and RXRα. Proteasome inhibitor MG132 blocked the inhibitory effect of HG on RARα and RXRα. Inhibition of intracellular reactive oxidative species (ROS) abolished the HG effect. In contrast, H(2)O(2) stimulation suppressed the expression and ligand-induced promoter activity of RARα and RXRα. HG promoted phosphorylation of ERK1/2, JNK and p38 MAP kinases, which was abrogated by an ROS inhibitor. Inhibition of JNK, but not ERK and p38 activity, reversed HG effects on RARα and RXRα. Activation of JNK by over expressing MKK7 and MEKK1, resulted in significant downregulation of RARα and RXRα. Ligand-induced promoter activity of RARα and RXRα was also suppressed by overexpression of MEKK1. HG-induced cardiomyocyte apoptosis was potentiated by activation of JNK, and prevented by all-trans retinoic acid and inhibition of JNK. Silencing the expression of RARα and RXRα activated the JNK pathway. In conclusion, HG-induced oxidative stress and activation of the JNK pathway negatively regulated expression/activation of RAR and RXR. The impaired RAR/RXR signaling and oxidative stress/JNK pathway forms a vicious circle, which significantly contributes to hyperglycemia induced cardiomyocyte apoptosis. SN - 1097-4652 UR - https://www.unboundmedicine.com/medline/citation/21882190/High_glucose_induced_repression_of_RAR/RXR_in_cardiomyocytes_is_mediated_through_oxidative_stress/JNK_signaling_ L2 - https://doi.org/10.1002/jcp.23005 DB - PRIME DP - Unbound Medicine ER -