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High glucose-induced repression of RAR/RXR in cardiomyocytes is mediated through oxidative stress/JNK signaling.
J Cell Physiol 2012; 227(6):2632-44JC

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.

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, Texas 76504, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

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 -