Exp Mol Med.  2009 Apr;41(4):243-252. 10.3858/emm.2009.41.4.027.

Involvement of GADD153 and cardiac ankyrin repeat protein in cardiac ischemia-reperfusion injury

• Lee MJ
• Kwak YK
• You KR
• Lee BH
• Kim DG

• KMID: 1088599
• DOI: http://doi.org/10.3858/emm.2009.41.4.027

Abstract

Oxidative stress is critical for causing cardiac injuries during ischemia-reperfusion (IR), yet the molecular mechanism for this remains unclear. In the present study, we observe that hypoxia and reoxygenation, a component of ischemia, effectively induces apoptosis in the cardiac myocytes from neonatal rats and it concomitantly leads to induction of GADD153, an apoptosis-related gene. Furthermore, IR injury of rat heart showed a GADD153 overexpression in the ischemic area where the TUNEL reaction was positive. A downregulation of cardiac ankyrin repeat protein (CARP) was also observed in this ischemic area. Promoter deletion and reporter analysis revealed that hypoxia transcriptionally activates a GADD153 promoter through the AP-1 element in neonatal cardiomyocytes. Ectopic overexpression of GADD153 resulted in the downregulation of CARP expression. Accordingly, the induction of GADD153 mRNA were followed by the CARP down-regulation in an in vivo rat coronary ischemia/reperfusion injury model. These results suggest that GADD153 over-expression and the resulting downregulation of CARP may have causative roles in apoptotic cell death during cardiac IR injury.

Keyword

ANKRD1 protein, human; apoptosis; heart; reperfusion injury; transcription factor CHOP

MeSH Terms

Animals
Animals, Newborn
Anoxia
Apoptosis/physiology
Cells, Cultured
Humans
Male
*Myocardial Reperfusion Injury/metabolism/pathology
*Myocardium/metabolism/pathology
Myocytes, Cardiac/cytology/metabolism
Nuclear Proteins/genetics/*metabolism
Promoter Regions, Genetic
Rats
Rats, Sprague-Dawley
Repressor Proteins/genetics/*metabolism
Transcription Factor AP-1/genetics/metabolism
Transcription Factor CHOP/genetics/*metabolism