Cardiovascular Research Advance Access [Accepted Manuscript] published online on January 15, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp015
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microRNA Expression in Response to Murine Myocardial Infarction: miR-21 Regulates Fibroblast MMP2 via PTEN
* Davis Heart & Lung Research Institute, Departments of Surgery and Pathology, The Ohio State University Medical Center, Columbus, Ohio 43210
Address correspondence to: Professor Chandan K. Sen 512 Davis Heart & Lung Research Institute 473 West 12th Avenue The Ohio State University Medical Center Columbus, Ohio 43210. Tel. 614 247 7658, Fax 614 247 7818. E.mail: Chandan.Sen{at}osumc.edu
Aims: MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression at the post-transcriptional level by either degradation or translational repression of a target mRNA. Encoded in the genome of most eukaryotes, miRNAs have been proposed to regulate specifically up to 90% of human genes through a process known as miRNA-guided RNA silencing. For the first time, we sought to test how myocardial ischemia-reperfusion (IR) changes miR expression.
Methods: Following 2h and 7h of IR or sham operation, myocardial tissue was collected and subjected to miRNA expression profiling and quantification using a Bioarray system that screens for human-, mice-, rat- and Ambi- miR. Data mining and differential analyses resulted in 14 miRs that were upregulated on day 2, 9 miRs that were upregulated on day 7 and 7 miRs that were down-regulated on day 7 post-IR. Results randomly selected from expression profiling were validated using real-time PCR.
Results: Tissue elements laser captured from the infarct site showed marked induction of miR-21. In situ hybridization studies using locked nucleic acid miR-21-specific probe identified that IR-inducible miR-21 was specifically localized in the infarct region of the IR heart. Immunohistochemistry data show that cardiac fibroblasts are the major cell type in the infarct zone. Studies with isolated CF demonstrated that phosphatase and tensin homolog (PTEN) is a direct target of miR-21. Modulation of miR-21 regulated expression of matrix metalloproteases 2 (MMP-2) via a PTEN pathway. Finally, we noted a marked decrease in PTEN expression in the infarct zone. This decrease was associated with increased MMP2 expression in the infarct area.
Conclusions: This work constitutes the first report describing changes in miR expression in response to ischemia-reperfusion (IR) in the mouse heart showing that miR21 regulates MMP2 expression in cardiac fibroblasts of the infarct zone via a PTEN pathway.
Time for primary review: 24 Days
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Cardiovasc Res 2009 82: 1-3.
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