Notch1 Mediates Preconditioning Protection Induced by GPER in Normotensive and Hypertensive Female Rat Hearts
G protein-coupled estrogen receptor (GPER) is an estrogen receptor expressed in the cardiovascular system. G1, a selective GPER ligand, exerts cardiovascular effects through activation of the PI3K-Akt pathway and Notch signaling in normotensive animals. Here, we investigated whether the G1/GPER inte...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-05-01
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| Series: | Frontiers in Physiology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fphys.2018.00521/full |
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| author | Carmine Rocca Saveria Femminò Giorgio Aquila Maria C. Granieri Ernestina M. De Francesco Teresa Pasqua Damiano C. Rigiracciolo Francesca Fortini Francesca Fortini Maria C. Cerra Maria C. Cerra Marcello Maggiolini Pasquale Pagliaro Pasquale Pagliaro Paola Rizzo Paola Rizzo Paola Rizzo Tommaso Angelone Tommaso Angelone Claudia Penna Claudia Penna |
| author_facet | Carmine Rocca Saveria Femminò Giorgio Aquila Maria C. Granieri Ernestina M. De Francesco Teresa Pasqua Damiano C. Rigiracciolo Francesca Fortini Francesca Fortini Maria C. Cerra Maria C. Cerra Marcello Maggiolini Pasquale Pagliaro Pasquale Pagliaro Paola Rizzo Paola Rizzo Paola Rizzo Tommaso Angelone Tommaso Angelone Claudia Penna Claudia Penna |
| author_sort | Carmine Rocca |
| collection | DOAJ |
| description | G protein-coupled estrogen receptor (GPER) is an estrogen receptor expressed in the cardiovascular system. G1, a selective GPER ligand, exerts cardiovascular effects through activation of the PI3K-Akt pathway and Notch signaling in normotensive animals. Here, we investigated whether the G1/GPER interaction is involved in the limitation of infarct size, and improvement of post-ischemic contractile function in female spontaneous hypertensive rat (SHR) hearts. In this model, we also studied Notch signaling and key components of survival pathway, namely PI3K-Akt, nitric oxide synthase (NOS) and mitochondrial K+-ATP (MitoKATP) channels. Rat hearts isolated from female SHR underwent 30 min of global, normothermic ischemia and 120 min of reperfusion. G1 (10 nM) alone or specific inhibitors of GPER, PI3K/NOS and MitoKATP channels co-infused with G1, just before I/R, were studied. The involvement of Notch1 was studied by Western blotting. Infarct size and left ventricular pressure were measured. To confirm endothelial-independent G1-induced protection by Notch signaling, H9c2 cells were studied with specific inhibitor, N-[N-(3,5 difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT, 5 μM), of this signaling. Using DAPT, we confirmed the involvement of G1/Notch signaling in limiting infarct size in heart of normotensive animals. In the hypertensive model, G1-induced reduction in infarct size and improvement of cardiac function were prevented by the inhibition of GPER, PI3K/NOS, and MitoKATP channels. The involvement of Notch was confirmed by western blot in the hypertensive model and by the specific inhibitor in the normotensive model and cardiac cell line. Our results suggest that GPERs play a pivotal role in mediating preconditioning cardioprotection in normotensive and hypertensive conditions. The G1-induced protection involves Notch1 and is able to activate the survival pathway in the presence of comorbidity. Several pathological conditions, including hypertension, reduce the efficacy of ischemic conditioning strategies. However, G1-induced protection can result in significant reduction of I/R injury also female in hypertensive animals. Further studies may ascertain the clinical translation of the present results. |
| first_indexed | 2024-04-13T12:18:01Z |
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| last_indexed | 2024-04-13T12:18:01Z |
| publishDate | 2018-05-01 |
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| series | Frontiers in Physiology |
| spelling | doaj.art-2914316f5ede47e8bbbfcd0764e7b8bc2022-12-22T02:47:18ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2018-05-01910.3389/fphys.2018.00521368307Notch1 Mediates Preconditioning Protection Induced by GPER in Normotensive and Hypertensive Female Rat HeartsCarmine Rocca0Saveria Femminò1Giorgio Aquila2Maria C. Granieri3Ernestina M. De Francesco4Teresa Pasqua5Damiano C. Rigiracciolo6Francesca Fortini7Francesca Fortini8Maria C. Cerra9Maria C. Cerra10Marcello Maggiolini11Pasquale Pagliaro12Pasquale Pagliaro13Paola Rizzo14Paola Rizzo15Paola Rizzo16Tommaso Angelone17Tommaso Angelone18Claudia Penna19Claudia Penna20Laboratory of Molecular and Cellular Cardiac Physiology, Department of Biology, Ecology and E.S., University of Calabria, Rende, ItalyDepartment of Biological and Clinical Sciences, University of Turin, Turin, ItalyDepartment of Medical Sciences, University of Ferrara, Ferrara, ItalyLaboratory of Molecular and Cellular Cardiac Physiology, Department of Biology, Ecology and E.S., University of Calabria, Rende, ItalyDepartment of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, ItalyLaboratory of Molecular and Cellular Cardiac Physiology, Department of Biology, Ecology and E.S., University of Calabria, Rende, ItalyDepartment of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, ItalyDepartment of Medical Sciences, University of Ferrara, Ferrara, ItalyMaria Cecilia Hospital, GVM Care & Research, E.S. Health Science Foundation, Cotignola, ItalyLaboratory of Molecular and Cellular Cardiac Physiology, Department of Biology, Ecology and E.S., University of Calabria, Rende, ItalyNational Institute for Cardiovascular Research, Bologna, ItalyDepartment of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, ItalyDepartment of Biological and Clinical Sciences, University of Turin, Turin, ItalyNational Institute for Cardiovascular Research, Bologna, ItalyMaria Cecilia Hospital, GVM Care & Research, E.S. Health Science Foundation, Cotignola, ItalyDepartment of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, ItalyLaboratory for Technologies of Advanced Therapies, University of Ferrara, Ferrara, ItalyLaboratory of Molecular and Cellular Cardiac Physiology, Department of Biology, Ecology and E.S., University of Calabria, Rende, ItalyNational Institute for Cardiovascular Research, Bologna, ItalyDepartment of Biological and Clinical Sciences, University of Turin, Turin, ItalyNational Institute for Cardiovascular Research, Bologna, ItalyG protein-coupled estrogen receptor (GPER) is an estrogen receptor expressed in the cardiovascular system. G1, a selective GPER ligand, exerts cardiovascular effects through activation of the PI3K-Akt pathway and Notch signaling in normotensive animals. Here, we investigated whether the G1/GPER interaction is involved in the limitation of infarct size, and improvement of post-ischemic contractile function in female spontaneous hypertensive rat (SHR) hearts. In this model, we also studied Notch signaling and key components of survival pathway, namely PI3K-Akt, nitric oxide synthase (NOS) and mitochondrial K+-ATP (MitoKATP) channels. Rat hearts isolated from female SHR underwent 30 min of global, normothermic ischemia and 120 min of reperfusion. G1 (10 nM) alone or specific inhibitors of GPER, PI3K/NOS and MitoKATP channels co-infused with G1, just before I/R, were studied. The involvement of Notch1 was studied by Western blotting. Infarct size and left ventricular pressure were measured. To confirm endothelial-independent G1-induced protection by Notch signaling, H9c2 cells were studied with specific inhibitor, N-[N-(3,5 difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT, 5 μM), of this signaling. Using DAPT, we confirmed the involvement of G1/Notch signaling in limiting infarct size in heart of normotensive animals. In the hypertensive model, G1-induced reduction in infarct size and improvement of cardiac function were prevented by the inhibition of GPER, PI3K/NOS, and MitoKATP channels. The involvement of Notch was confirmed by western blot in the hypertensive model and by the specific inhibitor in the normotensive model and cardiac cell line. Our results suggest that GPERs play a pivotal role in mediating preconditioning cardioprotection in normotensive and hypertensive conditions. The G1-induced protection involves Notch1 and is able to activate the survival pathway in the presence of comorbidity. Several pathological conditions, including hypertension, reduce the efficacy of ischemic conditioning strategies. However, G1-induced protection can result in significant reduction of I/R injury also female in hypertensive animals. Further studies may ascertain the clinical translation of the present results.http://journal.frontiersin.org/article/10.3389/fphys.2018.00521/fullcardioprotectionpreconditioningH9c2isolated rat heartsreperfusion injury salvage kinasesPI3K/Akt |
| spellingShingle | Carmine Rocca Saveria Femminò Giorgio Aquila Maria C. Granieri Ernestina M. De Francesco Teresa Pasqua Damiano C. Rigiracciolo Francesca Fortini Francesca Fortini Maria C. Cerra Maria C. Cerra Marcello Maggiolini Pasquale Pagliaro Pasquale Pagliaro Paola Rizzo Paola Rizzo Paola Rizzo Tommaso Angelone Tommaso Angelone Claudia Penna Claudia Penna Notch1 Mediates Preconditioning Protection Induced by GPER in Normotensive and Hypertensive Female Rat Hearts Frontiers in Physiology cardioprotection preconditioning H9c2 isolated rat hearts reperfusion injury salvage kinases PI3K/Akt |
| title | Notch1 Mediates Preconditioning Protection Induced by GPER in Normotensive and Hypertensive Female Rat Hearts |
| title_full | Notch1 Mediates Preconditioning Protection Induced by GPER in Normotensive and Hypertensive Female Rat Hearts |
| title_fullStr | Notch1 Mediates Preconditioning Protection Induced by GPER in Normotensive and Hypertensive Female Rat Hearts |
| title_full_unstemmed | Notch1 Mediates Preconditioning Protection Induced by GPER in Normotensive and Hypertensive Female Rat Hearts |
| title_short | Notch1 Mediates Preconditioning Protection Induced by GPER in Normotensive and Hypertensive Female Rat Hearts |
| title_sort | notch1 mediates preconditioning protection induced by gper in normotensive and hypertensive female rat hearts |
| topic | cardioprotection preconditioning H9c2 isolated rat hearts reperfusion injury salvage kinases PI3K/Akt |
| url | http://journal.frontiersin.org/article/10.3389/fphys.2018.00521/full |
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