Role of miR-133/Dio3 Axis in the T3-Dependent Modulation of Cardiac mitoK-ATP Expression
The opening of the ATP-sensitive mitochondrial potassium channel (mitok-ATP) is a common goal of cardioprotective strategies in the setting of acute and chronic myocardial disease. The biologically active thyroid hormone (TH), 3-5-3-triiodothyronine (T3), has been indicated as a potential activator...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-06-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/23/12/6549 |
| _version_ | 1797486600199864320 |
|---|---|
| author | Paola Canale Giuseppina Nicolini Letizia Pitto Claudia Kusmic Milena Rizzo Silvana Balzan Giorgio Iervasi Francesca Forini |
| author_facet | Paola Canale Giuseppina Nicolini Letizia Pitto Claudia Kusmic Milena Rizzo Silvana Balzan Giorgio Iervasi Francesca Forini |
| author_sort | Paola Canale |
| collection | DOAJ |
| description | The opening of the ATP-sensitive mitochondrial potassium channel (mitok-ATP) is a common goal of cardioprotective strategies in the setting of acute and chronic myocardial disease. The biologically active thyroid hormone (TH), 3-5-3-triiodothyronine (T3), has been indicated as a potential activator of mitoK-ATP but the underlying mechanisms are still elusive. Here we describe a novel role of T3 in the transcriptional regulation of mitoK and mitoSur, the recently identified molecular constituents of the channel. To mimic human ischemic heart damage, we used a rat model of a low T3 state as the outcome of a myocardial ischemia/reperfusion event, and neonatal rat cardiomyocytes (NRCM) challenged with hypoxia or H<sub>2</sub>O<sub>2</sub>. Either in the in vivo or in vitro models, T3 administration to recover the physiological concentrations was able to restore the expression level of both the channel subunits, which were found to be downregulated under the stress conditions. Furthermore, the T3-mediated transcriptional activation of mitoK-ATP in the myocardium and NRCM was associated with the repression of the TH-inactivating enzyme, deiodinase 3 (Dio3), and an up-regulation of the T3-responsive miR-133a-3p. Mechanistically, the loss and gain of function experiments and reporter gene assays performed in NRCM, have revealed a new regulatory axis whereby the silencing of Dio3 under the control of miR-133a-3p drives the T3-dependent modulation of cardiac mitoK and mitoSur transcription. |
| first_indexed | 2024-03-09T23:35:33Z |
| format | Article |
| id | doaj.art-e18834547f8c416aba3ca5ea96eba395 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T23:35:33Z |
| publishDate | 2022-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-e18834547f8c416aba3ca5ea96eba3952023-11-23T17:02:38ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-06-012312654910.3390/ijms23126549Role of miR-133/Dio3 Axis in the T3-Dependent Modulation of Cardiac mitoK-ATP ExpressionPaola Canale0Giuseppina Nicolini1Letizia Pitto2Claudia Kusmic3Milena Rizzo4Silvana Balzan5Giorgio Iervasi6Francesca Forini7CNR Institute of Clinical Physiology, Via G. Moruzzi1, 56124 Pisa, ItalyCNR Institute of Clinical Physiology, Via G. Moruzzi1, 56124 Pisa, ItalyCNR Institute of Clinical Physiology, Via G. Moruzzi1, 56124 Pisa, ItalyCNR Institute of Clinical Physiology, Via G. Moruzzi1, 56124 Pisa, ItalyCNR Institute of Clinical Physiology, Via G. Moruzzi1, 56124 Pisa, ItalyCNR Institute of Clinical Physiology, Via G. Moruzzi1, 56124 Pisa, ItalyCNR Institute of Clinical Physiology, Via G. Moruzzi1, 56124 Pisa, ItalyCNR Institute of Clinical Physiology, Via G. Moruzzi1, 56124 Pisa, ItalyThe opening of the ATP-sensitive mitochondrial potassium channel (mitok-ATP) is a common goal of cardioprotective strategies in the setting of acute and chronic myocardial disease. The biologically active thyroid hormone (TH), 3-5-3-triiodothyronine (T3), has been indicated as a potential activator of mitoK-ATP but the underlying mechanisms are still elusive. Here we describe a novel role of T3 in the transcriptional regulation of mitoK and mitoSur, the recently identified molecular constituents of the channel. To mimic human ischemic heart damage, we used a rat model of a low T3 state as the outcome of a myocardial ischemia/reperfusion event, and neonatal rat cardiomyocytes (NRCM) challenged with hypoxia or H<sub>2</sub>O<sub>2</sub>. Either in the in vivo or in vitro models, T3 administration to recover the physiological concentrations was able to restore the expression level of both the channel subunits, which were found to be downregulated under the stress conditions. Furthermore, the T3-mediated transcriptional activation of mitoK-ATP in the myocardium and NRCM was associated with the repression of the TH-inactivating enzyme, deiodinase 3 (Dio3), and an up-regulation of the T3-responsive miR-133a-3p. Mechanistically, the loss and gain of function experiments and reporter gene assays performed in NRCM, have revealed a new regulatory axis whereby the silencing of Dio3 under the control of miR-133a-3p drives the T3-dependent modulation of cardiac mitoK and mitoSur transcription.https://www.mdpi.com/1422-0067/23/12/6549mitoK-ATPmitoKmitoSurlow T3 statemiRNAcardiac ischemia/reperfusion |
| spellingShingle | Paola Canale Giuseppina Nicolini Letizia Pitto Claudia Kusmic Milena Rizzo Silvana Balzan Giorgio Iervasi Francesca Forini Role of miR-133/Dio3 Axis in the T3-Dependent Modulation of Cardiac mitoK-ATP Expression International Journal of Molecular Sciences mitoK-ATP mitoK mitoSur low T3 state miRNA cardiac ischemia/reperfusion |
| title | Role of miR-133/Dio3 Axis in the T3-Dependent Modulation of Cardiac mitoK-ATP Expression |
| title_full | Role of miR-133/Dio3 Axis in the T3-Dependent Modulation of Cardiac mitoK-ATP Expression |
| title_fullStr | Role of miR-133/Dio3 Axis in the T3-Dependent Modulation of Cardiac mitoK-ATP Expression |
| title_full_unstemmed | Role of miR-133/Dio3 Axis in the T3-Dependent Modulation of Cardiac mitoK-ATP Expression |
| title_short | Role of miR-133/Dio3 Axis in the T3-Dependent Modulation of Cardiac mitoK-ATP Expression |
| title_sort | role of mir 133 dio3 axis in the t3 dependent modulation of cardiac mitok atp expression |
| topic | mitoK-ATP mitoK mitoSur low T3 state miRNA cardiac ischemia/reperfusion |
| url | https://www.mdpi.com/1422-0067/23/12/6549 |
| work_keys_str_mv | AT paolacanale roleofmir133dio3axisinthet3dependentmodulationofcardiacmitokatpexpression AT giuseppinanicolini roleofmir133dio3axisinthet3dependentmodulationofcardiacmitokatpexpression AT letiziapitto roleofmir133dio3axisinthet3dependentmodulationofcardiacmitokatpexpression AT claudiakusmic roleofmir133dio3axisinthet3dependentmodulationofcardiacmitokatpexpression AT milenarizzo roleofmir133dio3axisinthet3dependentmodulationofcardiacmitokatpexpression AT silvanabalzan roleofmir133dio3axisinthet3dependentmodulationofcardiacmitokatpexpression AT giorgioiervasi roleofmir133dio3axisinthet3dependentmodulationofcardiacmitokatpexpression AT francescaforini roleofmir133dio3axisinthet3dependentmodulationofcardiacmitokatpexpression |