CHOP deficiency prevents methylglyoxal-induced myocyte apoptosis and cardiac dysfunction
- CHOP deficiency prevents methylglyoxal-induced myocyte apoptosis and cardiac dysfunction
- 우창훈; 남대환; 한정화; 이태진; Tetsuro Shishido[Tetsuro Shishido]; 임재향[임재향]; 김근영[김근영]
- ENDOPLASMIC-RETICULUM STRESS; C/EBP HOMOLOGOUS PROTEIN; GLYOXALASE-I OVEREXPRESSION; GLYCATION END-PRODUCTS; SPRAGUE-DAWLEY RATS; ER STRESS; DIABETES-MELLITUS; ENDOTHELIAL-CELLS; OXIDATIVE STRESS; HEART-DISEASE
- Issue Date
- ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
- JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, v.85, pp.168 - 177
- Epidemiological studies indicate that methylglyoxal (MGO) plasma levels are closely linked to diabetes and the exacerbation of diabetic cardiovascular complications. Recently, it was established that endoplasmic reticulum (ER) stress importantly contributes to the pathogenesis of diabetes and its cardiovascular complications. The objective of this study was to explore the mechanism by which diabetes instigates cardiomyocyte apoptosis and cardiac dysfunction via MGO-mediated myocyte apoptosis. Intriguingly, the MGO activated unfolded protein response pathway accompanying apoptotic events, such as cleavages of PARP-1 and caspase-3. In addition, Western blot analysis revealed that MGO-induced myocyte apoptosis was inhibited by depletion of CHOP with siRNA against Ddit3, the gene name for rat CHOP. To investigate the physiologic roles of CHOP in vivo, glucose tolerance and cardiac dysfunction were assessed in CHOP-deficient mice. No significant difference was observed between CHOP KO and littermate naive controls in terms of the MGO-induced impairment of glucose tolerance. In contrast, myocyte apoptosis, inflammation, and cardiac dysfunction were significantly diminished in CHOP KO compared with littermate na ve controls. These results showed that CHOP is the key signal for myocyte apoptosis and cardiac dysfunction induced by MGO. These findings suggest a therapeutic potential of CHOP inhibition in the management of diabetic cardiovascular complications including diabetic cardiomyopathy. (C) 2015 Elsevier Ltd. All rights reserved.
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