The Antioxidant Selenoprotein T Mimetic, PSELT, Induces Preconditioning-like Myocardial Protection by Relieving Endoplasmic-Reticulum Stress
Oxidative stress and endoplasmic reticulum stress (ERS) are strictly involved in myocardial ischemia/reperfusion (MI/R). Selenoprotein T (SELENOT), a vital thioredoxin-like selenoprotein, is crucial for ER homeostasis and cardiomyocyte differentiation and protection, likely acting as a redox-sensing...
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| Format: | Article |
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MDPI AG
2022-03-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/11/3/571 |
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| author | Carmine Rocca Anna De Bartolo Maria Concetta Granieri Vittoria Rago Daniela Amelio Flavia Falbo Rocco Malivindi Rosa Mazza Maria Carmela Cerra Loubna Boukhzar Benjamin Lefranc Jérôme Leprince Youssef Anouar Tommaso Angelone |
| author_facet | Carmine Rocca Anna De Bartolo Maria Concetta Granieri Vittoria Rago Daniela Amelio Flavia Falbo Rocco Malivindi Rosa Mazza Maria Carmela Cerra Loubna Boukhzar Benjamin Lefranc Jérôme Leprince Youssef Anouar Tommaso Angelone |
| author_sort | Carmine Rocca |
| collection | DOAJ |
| description | Oxidative stress and endoplasmic reticulum stress (ERS) are strictly involved in myocardial ischemia/reperfusion (MI/R). Selenoprotein T (SELENOT), a vital thioredoxin-like selenoprotein, is crucial for ER homeostasis and cardiomyocyte differentiation and protection, likely acting as a redox-sensing protein during MI/R. Here, we designed a small peptide (PSELT), encompassing the redox site of SELENOT, and investigated whether its pre-conditioning cardioprotective effect resulted from modulating ERS during I/R. The Langendorff rat heart model was employed for hemodynamic analysis, while mechanistic studies were performed in perfused hearts and H9c2 cardiomyoblasts. PSELT improved the post-ischemic contractile recovery, reducing infarct size and LDH release with and without the ERS inducer tunicamycin (TM). Mechanistically, I/R and TM upregulated SELENOT expression, which was further enhanced by PSELT. PSELT also prevented the expression of the ERS markers CHOP and ATF6, reduced cardiac lipid peroxidation and protein oxidation, and increased SOD and catalase activities. An inert PSELT (I-PSELT) lacking selenocysteine was ineffective. In H9c2 cells, H<sub>2</sub>O<sub>2</sub> decreased cell viability and SELENOT expression, while PSELT rescued protein levels protecting against cell death. In SELENOT-deficient H9c2 cells, H<sub>2</sub>O<sub>2</sub> exacerbated cell death, that was partially mitigated by PSELT. Microscopy analysis revealed that a fluorescent form of PSELT was internalized into cardiomyocytes with a perinuclear distribution. <i>Conclusions:</i> The cell-permeable PSELT is able to induce pharmacological preconditioning cardioprotection by mitigating ERS and oxidative stress, and by regulating endogenous SELENOT. |
| first_indexed | 2024-03-09T20:10:25Z |
| format | Article |
| id | doaj.art-306edd29babd40a29ca28201f8402450 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-09T20:10:25Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-306edd29babd40a29ca28201f84024502023-11-24T00:18:57ZengMDPI AGAntioxidants2076-39212022-03-0111357110.3390/antiox11030571The Antioxidant Selenoprotein T Mimetic, PSELT, Induces Preconditioning-like Myocardial Protection by Relieving Endoplasmic-Reticulum StressCarmine Rocca0Anna De Bartolo1Maria Concetta Granieri2Vittoria Rago3Daniela Amelio4Flavia Falbo5Rocco Malivindi6Rosa Mazza7Maria Carmela Cerra8Loubna Boukhzar9Benjamin Lefranc10Jérôme Leprince11Youssef Anouar12Tommaso Angelone13Laboratory of Cellular and Molecular Cardiovascular Pathophysiology, Department of Biology, Ecology and Earth Sciences (DiBEST), University of Calabria, 87036 Rende, ItalyLaboratory of Cellular and Molecular Cardiovascular Pathophysiology, Department of Biology, Ecology and Earth Sciences (DiBEST), University of Calabria, 87036 Rende, ItalyLaboratory of Cellular and Molecular Cardiovascular Pathophysiology, Department of Biology, Ecology and Earth Sciences (DiBEST), University of Calabria, 87036 Rende, ItalyDepartment of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, ItalyLaboratory of Organ and System Physiology, Department of Biology, Ecology and Earth Sciences (DiBEST), University of Calabria, 87036 Rende, ItalyLaboratory of Cellular and Molecular Cardiovascular Pathophysiology, Department of Biology, Ecology and Earth Sciences (DiBEST), University of Calabria, 87036 Rende, ItalyDepartment of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, ItalyLaboratory of Organ and System Physiology, Department of Biology, Ecology and Earth Sciences (DiBEST), University of Calabria, 87036 Rende, ItalyLaboratory of Organ and System Physiology, Department of Biology, Ecology and Earth Sciences (DiBEST), University of Calabria, 87036 Rende, ItalyUNIROUEN, Inserm U1239, Neuroendocrine, Endocrine and Germinal Differentiation and Communication (NorDiC), Rouen Normandie University, 76821 Mont-Saint-Aignan, FranceUNIROUEN, Inserm U1239, Neuroendocrine, Endocrine and Germinal Differentiation and Communication (NorDiC), Rouen Normandie University, 76821 Mont-Saint-Aignan, FranceUNIROUEN, Inserm U1239, Neuroendocrine, Endocrine and Germinal Differentiation and Communication (NorDiC), Rouen Normandie University, 76821 Mont-Saint-Aignan, FranceUNIROUEN, Inserm U1239, Neuroendocrine, Endocrine and Germinal Differentiation and Communication (NorDiC), Rouen Normandie University, 76821 Mont-Saint-Aignan, FranceLaboratory of Cellular and Molecular Cardiovascular Pathophysiology, Department of Biology, Ecology and Earth Sciences (DiBEST), University of Calabria, 87036 Rende, ItalyOxidative stress and endoplasmic reticulum stress (ERS) are strictly involved in myocardial ischemia/reperfusion (MI/R). Selenoprotein T (SELENOT), a vital thioredoxin-like selenoprotein, is crucial for ER homeostasis and cardiomyocyte differentiation and protection, likely acting as a redox-sensing protein during MI/R. Here, we designed a small peptide (PSELT), encompassing the redox site of SELENOT, and investigated whether its pre-conditioning cardioprotective effect resulted from modulating ERS during I/R. The Langendorff rat heart model was employed for hemodynamic analysis, while mechanistic studies were performed in perfused hearts and H9c2 cardiomyoblasts. PSELT improved the post-ischemic contractile recovery, reducing infarct size and LDH release with and without the ERS inducer tunicamycin (TM). Mechanistically, I/R and TM upregulated SELENOT expression, which was further enhanced by PSELT. PSELT also prevented the expression of the ERS markers CHOP and ATF6, reduced cardiac lipid peroxidation and protein oxidation, and increased SOD and catalase activities. An inert PSELT (I-PSELT) lacking selenocysteine was ineffective. In H9c2 cells, H<sub>2</sub>O<sub>2</sub> decreased cell viability and SELENOT expression, while PSELT rescued protein levels protecting against cell death. In SELENOT-deficient H9c2 cells, H<sub>2</sub>O<sub>2</sub> exacerbated cell death, that was partially mitigated by PSELT. Microscopy analysis revealed that a fluorescent form of PSELT was internalized into cardiomyocytes with a perinuclear distribution. <i>Conclusions:</i> The cell-permeable PSELT is able to induce pharmacological preconditioning cardioprotection by mitigating ERS and oxidative stress, and by regulating endogenous SELENOT.https://www.mdpi.com/2076-3921/11/3/571antioxidantsheartischemia/reperfusion injurypeptidesselenoproteins |
| spellingShingle | Carmine Rocca Anna De Bartolo Maria Concetta Granieri Vittoria Rago Daniela Amelio Flavia Falbo Rocco Malivindi Rosa Mazza Maria Carmela Cerra Loubna Boukhzar Benjamin Lefranc Jérôme Leprince Youssef Anouar Tommaso Angelone The Antioxidant Selenoprotein T Mimetic, PSELT, Induces Preconditioning-like Myocardial Protection by Relieving Endoplasmic-Reticulum Stress Antioxidants antioxidants heart ischemia/reperfusion injury peptides selenoproteins |
| title | The Antioxidant Selenoprotein T Mimetic, PSELT, Induces Preconditioning-like Myocardial Protection by Relieving Endoplasmic-Reticulum Stress |
| title_full | The Antioxidant Selenoprotein T Mimetic, PSELT, Induces Preconditioning-like Myocardial Protection by Relieving Endoplasmic-Reticulum Stress |
| title_fullStr | The Antioxidant Selenoprotein T Mimetic, PSELT, Induces Preconditioning-like Myocardial Protection by Relieving Endoplasmic-Reticulum Stress |
| title_full_unstemmed | The Antioxidant Selenoprotein T Mimetic, PSELT, Induces Preconditioning-like Myocardial Protection by Relieving Endoplasmic-Reticulum Stress |
| title_short | The Antioxidant Selenoprotein T Mimetic, PSELT, Induces Preconditioning-like Myocardial Protection by Relieving Endoplasmic-Reticulum Stress |
| title_sort | antioxidant selenoprotein t mimetic pselt induces preconditioning like myocardial protection by relieving endoplasmic reticulum stress |
| topic | antioxidants heart ischemia/reperfusion injury peptides selenoproteins |
| url | https://www.mdpi.com/2076-3921/11/3/571 |
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