title: MicroRNA 214 Is a Potential Regulator of Thyroid Hormone Levels in the Mouse Heart Following Myocardial Infarction, by Targeting the Thyroid-Hormone-Inactivating Enzyme Deiodinase Type III.
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.
authors.affiliation: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center , Amsterdam , Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Janssen
authors.affiliation: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center , Amsterdam , Netherlands.
authors.forename: Marian J
authors.initials: MJ
authors.lastname: Zuidwijk
authors.affiliation: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center , Amsterdam , Netherlands.
authors.forename: Alice
authors.initials: A
authors.lastname: Muller
authors.affiliation: Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht , Utrecht , Netherlands.
authors.forename: Alain
authors.initials: A
authors.lastname: van Mil
authors.affiliation: Department of Cardiology, Faculty of Health, Medicine and Life Sciences, CARIM School for Cardiovascular Diseases, Maastricht University , Maastricht , Netherlands.
authors.forename: Ellen
authors.initials: E
authors.lastname: Dirkx
authors.affiliation: Department of Clinical Chemistry, Institute for Cardiovascular Research, VU University Medical Center , Amsterdam , Netherlands.
authors.forename: Cees B M
authors.initials: CB
authors.lastname: Oudejans
authors.affiliation: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center , Amsterdam , Netherlands.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Paulus
authors.affiliation: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center , Amsterdam , Netherlands.
authors.forename: Warner S
authors.initials: WS
authors.lastname: Simonides
keywords: Dio3; SECIS; microRNA; myocardial infarction; thyroid hormone metabolism