PMID- 21882190
OWN - NLM
STAT- MEDLINE
DCOM- 20120419
LR  - 20220321
IS  - 1097-4652 (Electronic)
IS  - 0021-9541 (Print)
IS  - 0021-9541 (Linking)
VI  - 227
IP  - 6
DP  - 2012 Jun
TI  - High glucose-induced repression of RAR/RXR in cardiomyocytes is mediated through 
      oxidative stress/JNK signaling.
PG  - 2632-44
LID - 10.1002/jcp.23005 [doi]
AB  - 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 RARalpha and RXRalpha has an important role in high glucose 
      (HG)-induced cardiomyocyte apoptosis. However, the regulatory mechanisms of HG 
      effects on RARalpha and RXRalpha 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 RARalpha and 
      RXRalpha. Proteasome inhibitor MG132 blocked the inhibitory effect of HG on RARalpha and 
      RXRalpha. 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 RARalpha and RXRalpha. 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 RARalpha and 
      RXRalpha. Activation of JNK by over expressing MKK7 and MEKK1, resulted in 
      significant downregulation of RARalpha and RXRalpha. Ligand-induced promoter activity of 
      RARalpha and RXRalpha 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 RARalpha 
      and RXRalpha 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.
CI  - Copyright (c) 2011 Wiley Periodicals, Inc.
FAU - Singh, Amar B
AU  - Singh AB
AD  - 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.
FAU - Guleria, Rakeshwar S
AU  - Guleria RS
FAU - Nizamutdinova, Irina T
AU  - Nizamutdinova IT
FAU - Baker, Kenneth M
AU  - Baker KM
FAU - Pan, Jing
AU  - Pan J
LA  - eng
GR  - R01 HL091902/HL/NHLBI NIH HHS/United States
GR  - R01 HL091902-01A1/HL/NHLBI NIH HHS/United States
GR  - 1R01 HL091902/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - J Cell Physiol
JT  - Journal of cellular physiology
JID - 0050222
RN  - 0 (Cysteine Proteinase Inhibitors)
RN  - 0 (Oxidants)
RN  - 0 (Proteasome Inhibitors)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (RARA protein, human)
RN  - 0 (Rara protein, rat)
RN  - 0 (Receptors, Retinoic Acid)
RN  - 0 (Retinoic Acid Receptor alpha)
RN  - 0 (Retinoid X Receptor alpha)
RN  - 1UA8E65KDZ (Alitretinoin)
RN  - 5688UTC01R (Tretinoin)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.25 (MAP Kinase Kinase Kinase 1)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 7)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Alitretinoin
MH  - Animals
MH  - Animals, Newborn
MH  - Apoptosis
MH  - Cysteine Proteinase Inhibitors/pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Glucose/*metabolism
MH  - HEK293 Cells
MH  - Humans
MH  - Hyperglycemia/*enzymology/genetics/pathology
MH  - JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors/*metabolism
MH  - MAP Kinase Kinase 7/genetics/metabolism
MH  - MAP Kinase Kinase Kinase 1/genetics/metabolism
MH  - Mitogen-Activated Protein Kinase 1/metabolism
MH  - Mitogen-Activated Protein Kinase 3/metabolism
MH  - Myocytes, Cardiac/drug effects/*enzymology/pathology
MH  - Oxidants/pharmacology
MH  - *Oxidative Stress/drug effects
MH  - Phosphorylation
MH  - Promoter Regions, Genetic
MH  - Proteasome Endopeptidase Complex/metabolism
MH  - Proteasome Inhibitors
MH  - Protein Kinase Inhibitors/pharmacology
MH  - RNA Interference
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, Retinoic Acid/agonists/genetics/*metabolism
MH  - Retinoic Acid Receptor alpha
MH  - Retinoid X Receptor alpha/agonists/genetics/*metabolism
MH  - *Signal Transduction/drug effects
MH  - Time Factors
MH  - Transcriptional Activation
MH  - Transfection
MH  - Tretinoin/pharmacology
MH  - p38 Mitogen-Activated Protein Kinases/metabolism
PMC - PMC3258345
MID - NIHMS322695
EDAT- 2011/09/02 06:00
MHDA- 2012/04/20 06:00
PMCR- 2013/06/01
CRDT- 2011/09/02 06:00
PHST- 2011/09/02 06:00 [entrez]
PHST- 2011/09/02 06:00 [pubmed]
PHST- 2012/04/20 06:00 [medline]
PHST- 2013/06/01 00:00 [pmc-release]
AID - 10.1002/jcp.23005 [doi]
PST - ppublish
SO  - J Cell Physiol. 2012 Jun;227(6):2632-44. doi: 10.1002/jcp.23005.