Abstract
Cardiac thyroid-hormone signaling is a critical determinant of cellular metabolism and function in health and disease. A local hypothyroid condition within the failing heart in rodents has been associated with the re-expression of the fetally expressed thyroid-hormone-inactivating enzyme deiodinase type III (Dio3). While this enzyme emerges as a common denominator in the development of heart failure, the mechanism underlying its regulation remains largely unclear. In the present study, we investigated the involvement of microRNAs (miRNAs) in the regulation of Dio3 mRNA expression in the remodeling left ventricle (LV) of the mouse heart following myocardial infarction (MI). In silico analysis indicated that of the miRNAs that are differentially expressed in the post-MI heart, miR-214 has the highest potential to target Dio3 mRNA. In accordance, a luciferase reporter assay, including the full-length 3′UTR of mouse Dio3 mRNA, showed a 30% suppression of luciferase activity by miR-214. In the post-MI mouse heart, miR-214 and Dio3 protein were shown to be co-expressed in cardiomyocytes, while time-course analysis revealed that Dio3 mRNA expression precedes miR-214 expression in the post-MI LV. This suggests that a Dio3-induced decrease of T3 levels is involved in the induction of miR-214, which was supported by the finding that cardiac miR-214 expression is down regulated by T3 in mice. In vitro analysis of human DIO3 mRNA furthermore showed that miR-214 is able to suppress both mRNA and protein expression. Dio3 mRNA is a target of miR-214 and the Dio3-dependent stimulation of miR-214 expression in post-MI cardiomyocytes supports the involvement of a negative feedback mechanism regulating Dio3 expression.
Highlights
Myocardial infarction (MI) is one of the major causes of heart failure in Western society [1]
To identify potential miRNAs involved in regulating Dio3 expression in the remodeling left ventricle (LV), we performed in silico analysis using four different prediction databases
We identified miR-214 as a differentially regulated miRNA in the remodeling LV of the post-MI mouse heart compared to the LV of sham-operated mice, using TaqMan Megaplex array analysis of all 641 mouse miRNAs known at the time
Summary
Myocardial infarction (MI) is one of the major causes of heart failure in Western society [1]. The sudden interruption of blood flow results in cardiomyocyte death by necrosis and subsequent fibrosis of the affected part of the left ventricle (LV). The associated increase in cardiac load of the non-infarcted region of the heart triggers functional and structural remodeling of the spared myocardium aimed at maintaining cardiac output [2, 3]. Progressive remodeling, LV dilation, and the associated increase in wall stress often culminate in chronic heart failure. The underlying changes in gene expression are mediated by a multitude of signal transduction pathways involving transcriptional regulation, as well as non-coding transcripts, such as microRNAs (miRNAs), that affect mRNA stability or translation efficiency [3,4,5,6]
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