Involvement of GADD153 and cardiac ankyrin repeat protein in cardiac ischemia-reperfusion injury.
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.
Lee
Mi Jin
MJ
Department of Internal Medicine, Chonbuk National University Medical School and Hospital, Jeonju 561-712, Korea.
Kwak
Yong Keun
YK
You
Kyung Ran
KR
Lee
Byung Ho
BH
Kim
Dae Ghon
DG
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology; D002478:Cells, Cultured; D006801:Humans; D000860:Hypoxia; D008297:Male; D009124:Muscle Proteins; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism*
C491303:Ankrd1 protein, rat; C497251:Ddit3 protein, rat; D009124:Muscle Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D018808:Transcription Factor AP-1; D051742:Transcription Factor CHOP