科研之友
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摘要
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 RARa and RXRa has an important role in high glucose (HG)-induced cardiomyocyte apoptosis. However, the regulatory mechanisms of HG effects on RARa and RXRa 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 RARa and RXRa. Proteasome inhibitor MG132 blocked the inhibitory effect of HG on RARa and RXRa. Inhibition of intracellular reactive oxidative species (ROS) abolished the HG effect. In contrast, H2O2 stimulation suppressed the expression and ligand-induced promoter activity of RARa and RXRa. 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 RARa and RXRa. Activation of JNK by over expressing MKK7 and MEKK1, resulted in significant downregulation of RARa and RXRa. Ligand-induced promoter activity of RARa and RXRa 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 RARa and RXRa 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. J. Cell. Physiol. 227: 26322644, 2012.
- 出版日期2012-6
