High glucose-induced repression of RAR/RXR in cardiomyocytes is mediated through oxidative stress/JNK signaling.
High glucose-induced repression of RAR/RXR in cardiomyocytes is mediated through oxidative stress/JNK signaling.
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DOI：
10.1002/jcp.23005
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发表时间：
2012-06
影响因子：
5.6
通讯作者：
Pan, Jing
中科院分区：
文献类型：
--
作者：
Singh, Amar B.;Guleria, Rakeshwar S.;Nizamutdinova, Irina T.;Baker, Kenneth M.;Pan, Jing
类维生素A的生物学作用由核维甲酸受体（RAR）和类维生素A ×受体（RXR）介导。近年来，我们发现RARα和RXRα的表达降低在高糖诱导的心肌细胞凋亡中起重要作用。然而，HG对RARα和RXRα的调节机制尚不清楚。使用新生心肌细胞，我们发现，配体诱导的RAR和RXR的启动子活性显着抑制HG。HG促进RARα和RXRα的蛋白质去稳定化和丝氨酸磷酸化。蛋白酶体抑制剂MG 132可阻断HG对RARα和RXRα的抑制作用。细胞内活性氧化物质（ROS）的抑制消除HG的影响。相反，H2 O2刺激抑制RARα和RXRα的表达和配体诱导的启动子活性。HG促进ERK 1/2、JNK和p38 MAP激酶的磷酸化，这被ROS抑制剂消除。抑制JNK而非ERK和p38活性可逆转HG对RARα和RXRα的作用。通过过度表达MKK 7和MEKK 1激活JNK，导致RARα和RXRα的显著下调。配体诱导的RARα和RXRα的启动子活性也被MEKK 1的过表达抑制。HG诱导的心肌细胞凋亡可通过激活JNK而增强，ATRA和抑制JNK可阻止HG诱导的心肌细胞凋亡。沉默RARα和RXRα的表达激活了JNK通路。总之，HG诱导的氧化应激和JNK通路的激活负调节RAR和RXR的表达/激活。RAR/RXR信号通路和氧化应激/JNK信号通路的受损形成恶性循环，在高血糖诱导的心肌细胞凋亡中发挥重要作用。
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.
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DOI：
10.1080/07315724.1997.10718647
发表时间：
1997-02-01
影响因子：
3.5
作者：
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