Abstract 18709: MicroRNA Target Regulation is Cell Type Specific and is Influenced by Stress Conditions
MicroRNAs (miRs) modulate gene expression by repressing translation or inducing degradation of targeted mRNAs. Although miRs are currently explored as novel therapeutic targets, the cell type and context-specific effects of miRs in the heart are not well explored. Therefore, we determined target regulation using miR-92a as an example. Inhibition of miR-92a was shown to augment neovascularization and recovery after acute myocardial infarction (MI).
We performed microarrays using RNA isolated from the apex of control mice (n=4), healthy mice treated with the miR-92a-inhibitior LNA-92a (2.5 mg/kg) (n=4), and mice at 4 days after MI treated with either PBS (n=4) or LNA-92a (n=3). miR-92a was inhibited by more than 95 % in all LNA-92a-treated mice. In LNA-92a treated control mice, 73 genes including only one predicted miR-92a target were significantly regulated. In mice after MI, 310 genes (fold change<+/-1.4;p<0.05) were regulated by LNA-92a including 36 predicted miR-92a targets such as cardioprotective Hmox1 and the transcription factor Id2, which is involved in organ regeneration. A subset of 10 candidates was validated by qRT-PCR. Consistent with a more profound regulation of miR-92a targets after MI, miR-92a was enriched by 2-fold in the risk complex in the infarct tissue compared to remote or healthy tissue. Since miRs might exhibit distinct effects in specific cell types, we additionally isolated cell populations from mouse hearts after MI and determined gene expression by RNA sequencing. LNA-92a treatment upregulates 64 predicted miR-92a targets in cardiomyocytes, 68 in endothelial cells, 63 in fibroblasts, whereas only 17 predicted targets were regulated in immune cells. Most targets were regulated in a cell type specific manner and none was regulated in all cell types.
In conclusion, miR-92a inhibition has context and cell type specific effects in the heart. The more profound regulation of miR-92a targets and enrichment of miR-92a in the risk complex in infarcted tissue suggests that tissue injury amplifies the response to miR-92a inhibition. The cell type specific regulation of miR-92a targets implies that deciphering the specific functions of a given miR in cell populations is essential to understand the overall impact of miRs in complex tissues.
Author Disclosures: E. Kremp: None. G. La Rocca: None. A. Bonauer: None. A. Fischer: None. A.M. Zeiher: None. S. Dimmeler: None.
- © 2016 by American Heart Association, Inc.