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 × 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, H2O2 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 ATRA 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.

IGFBP5 mediates high glucose-induced cardiac fibroblast activation

“…Although high glucose presently did not increase IGFBP5 protein levels in cardiomyocytes, the IGFBP5 released from cardiac fibroblasts may promote the apoptosis of cardiac myocytes. The IGFBP5-mediated increase in JNK phosphorylation observed in our study also supports a proapoptotic effect of IGFBP5, as JNK is involved in high glucose-induced apoptosis in cardiomyocytes (Kuo et al 2012, Singh et al 2012. JNK may mediate IGFBP5-induced apoptosis in cardiomyocytes.…”

A Systems Approach for Decoding Mitochondrial Retrograde Signaling Pathways

“…This pathway also involved ROS, c-JUN N-terminal kinase (JNK), and a peroxisome proliferator-activated receptor g, coactivator 1 a (PGC1a) and contributed to the decrease in mRNA abundances of nuclear-encoded OXPHOS enzymes, which would further aggravate OXPHOS dysfunction caused by the mt3243 mutation. Although the negative regulation of RXRA abundance through JNK activated by ROS (11) and the interaction between RXRA and PGC1a (12) have been previously reported, the connection of this pathway to mitochondrial retrograde signaling has not. Here, we demonstrated that (i) mitochondrial dysfunctions decreased RXRA abundance, (ii) the reduction in RXRA decreased the interaction between RXRA and PGC1a, (iii) the reduced interaction contributed to the decrease in mRNA abundances of OXPHOS and translation-related genes, and (iv) the reduction of OXPHOS and translation-related genes was reversed by the addition of retinoic acid (RA).…”

The Function of Retinoid X Receptor α in Cancer Cells

“…RXRα/RAR heterodimers play a role in the retinoid-stimulated increase in steroid sulfatase activity which was blocked by pharmacological inhibition of the RAF-1 and ERK MAP kinases [52]. Accumulating evidence that ligand-induced promoter activity of RXRα/RAR heterodimer is significantly suppressed by high glucose (HG) which promoted protein destabilization and serine-phosphorylation of RAR and RXR is mediated through oxidative stress/JNK signaling [53]. The impaired RXRα/RAR signaling and oxidative stress/JNK pathway forms a vicious circle, which significantly contributes to cardiomyocyte apoptosis induced by hyperglycemia [53].…”

“…Accumulating evidence that ligand-induced promoter activity of RXRα/RAR heterodimer is significantly suppressed by high glucose (HG) which promoted protein destabilization and serine-phosphorylation of RAR and RXR is mediated through oxidative stress/JNK signaling [53]. The impaired RXRα/RAR signaling and oxidative stress/JNK pathway forms a vicious circle, which significantly contributes to cardiomyocyte apoptosis induced by hyperglycemia [53]. The RXRα/RAR signaling pathway plays critical roles in hippocampal synaptic plasticity and greatly contributes to memory performance, and long-term potentiation (LTP) in the hippocampus in the adult brain [54].…”