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Synergistic effects of the GATA-4-mediated miR-144/451 cluster in protection against simulated ischemia/reperfusion-induced cardiomyocyte death
- Source :
-
Journal of Molecular & Cellular Cardiology . Nov2010, Vol. 49 Issue 5, p841-850. 10p. - Publication Year :
- 2010
-
Abstract
- Abstract: Among the identified microRNAs (miRs) thus far, ~50% of mammalian miRs are clustered in the genome and transcribed as polycistronic primary transcripts. However, whether clustered miRs mediate non-redundant and cooperative functions remains poorly understood. In this study, we first identified activation of the promoter of miR-144/451 by GATA-4, a critical transcription factor in the heart. Next, we observed that ectopic expression of miR-144 and -451 individually augmented cardiomyocyte survival, which was further improved by overexpression of miR-144/451, compared to control cells in response to simulated ischemia/reperfusion. In contrast, knockdown of endogenous miR-144 and -451 revealed opposite effects. Using luciferase reporter assay and western blot analysis, we also validated that both miR-144 and miR-451 target CUG triplet repeat-binding protein 2 (CUGBP2), a ubiquitously expressed RNA-binding protein, known to interact with COX-2 3′UTR and inhibit its translation. Accordingly, protein levels of CUGBP2 were greatly reduced and COX-2 activity was markedly increased in miR-144-, miR-451-, and miR-144/451-overexpressing cardiomyocytes, compared to GFP cells. Furthermore, inhibition of COX-2 activity by either NS-398 or DUP-697 partially offset protective effects of the miR-144/451 cluster. Together, these data indicate that both partners of the miR-144/451 cluster confer protection against simulated I/R-induced cardiomyocyte death via targeting CUGBP2–COX-2 pathway, at least in part. Thus, both miR-144 and miR-451 may represent new therapeutic agents for the treatment of ischemic heart disease. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00222828
- Volume :
- 49
- Issue :
- 5
- Database :
- Academic Search Index
- Journal :
- Journal of Molecular & Cellular Cardiology
- Publication Type :
- Academic Journal
- Accession number :
- 54098571
- Full Text :
- https://doi.org/10.1016/j.yjmcc.2010.08.007