Gadd45beta is a novel mediator of cardiomyocyte apoptosis induced by ischaemia/hypoxia.
OBJECTIVE
Because apoptotic death plays a critical role in cardiomyocyte loss during ischaemic heart injury, a detailed understanding of the mechanisms involved is likely to have a substantial impact on the optimization and development of treatment strategies. The goal of this study was to assess gene profiling during ischaemia/hypoxia and to evaluate the functions of ischaemia/hypoxia-responsive genes in in vivo and in vitro ischaemia/hypoxia-induced cardiomyocyte apoptosis models.


RESULTS
DNA microarray analysis and real-time polymerase chain reaction were performed on hearts obtained from an in vivo rat transient ischaemia model and on neonatal rat cardiomyocytes from an in vitro hypoxia model. Three genes, namely Ddit4, Gadd45beta and Atf3, were found to be up-regulated in vivo and in vitro. Using loss-of-function and gain-of-function techniques, the functions of these ischaemia/hypoxia-responsive genes were evaluated. Ischaemia/hypoxia-induced cardiomyocyte apoptosis was remarkably attenuated by the small interfering RNA-mediated down-regulation of Gadd45beta in vivo and in vitro, whereas ectopic Gadd45beta expression significantly aggravated hypoxia-induced apoptosis in vitro.


CONCLUSIONS
These results suggest that Gadd45beta is a key player in ischaemia/hypoxia-induced apoptotic cardiomyocyte death, and that strategies based on its inhibition might be of benefit in the treatment of acute ischaemic heart disease.
Department of Physiology, School of Medicine, Ajou University, Suwon 443-749, Republic of Korea.
Mi-Young
MY
Kim
Eun Ji
EJ
Seo
Dong Ha
DH
Lee
Eun Joo
EJ
Kim
Hye Soo
HS
Kim
Hea-Young
HY
Cho
Eun Yong
EY
Chung
Soo Hwan
SH
Lee
Eun Joo
EJ
Baik
Chang-Hyun
CH
Moon
Yi-Sook
YS
Jung
D051700:Activating Transcription Factor 3 / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D000943:Antigens, Differentiation / Q000235:genetics* / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics; D015687:Cell Hypoxia; D002460:Cell Line; D004195:Disease Models, Animal; D020869:Gene Expression Profiling / Q000379:methods; D055785:Gene Knockdown Techniques; D006439:Hemodynamics; D008297:Male; D017202:Myocardial Ischemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000235:genetics; D013997:Time Factors; D014157:Transcription Factors; D014162:Transfection; D015854:Up-Regulation; D000097642:GADD45 Proteins
D051700:Activating Transcription Factor 3; D000943:Antigens, Differentiation; D012097:Repressor Proteins; D014157:Transcription Factors; C497108:Atf3 protein, rat; C000632146:Ddit4 protein, rat; C508094:Gadd45b protein, rat; D000097642:GADD45 Proteins