Effects of the Delta Opioid Receptor Agonist DADLE in a Novel Hypoxia-Reoxygenation Model on Human and Rat-Engineered Heart Tissue: A Pilot Study
Intermittent hypoxia and various pharmacological compounds protect the heart from ischemia reperfusion injury in experimental approaches, but the translation into clinical trials has largely failed. One reason may lie in species differences and the lack of suitable human in vitro models to test for...
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| Format: | Article |
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MDPI AG
2020-09-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/10/9/1309 |
| _version_ | 1797554026204626944 |
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| author | Sandra Funcke Tessa R. Werner Marc Hein Bärbel M. Ulmer Arne Hansen Thomas Eschenhagen Marc N. Hirt |
| author_facet | Sandra Funcke Tessa R. Werner Marc Hein Bärbel M. Ulmer Arne Hansen Thomas Eschenhagen Marc N. Hirt |
| author_sort | Sandra Funcke |
| collection | DOAJ |
| description | Intermittent hypoxia and various pharmacological compounds protect the heart from ischemia reperfusion injury in experimental approaches, but the translation into clinical trials has largely failed. One reason may lie in species differences and the lack of suitable human in vitro models to test for ischemia/reperfusion. We aimed to develop a novel hypoxia-reoxygenation model based on three-dimensional, spontaneously beating and work performing engineered heart tissue (EHT) from rat and human cardiomyocytes. Contractile force, the most important cardiac performance parameter, served as an integrated outcome measure. EHTs from neonatal rat cardiomyocytes were subjected to 90 min of hypoxia which led to cardiomyocyte apoptosis as revealed by caspase 3-staining, increased troponin I release (time control vs. 24 h after hypoxia: cTnI 2.7 vs. 6.3 ng/mL, ** <i>p</i> = 0.002) and decreased contractile force (64 ± 6% of baseline) in the long-term follow-up. The detrimental effects were attenuated by preceding the long-term hypoxia with three cycles of 10 min hypoxia (i.e., hypoxic preconditioning). Similarly, [<span style="font-variant: small-caps;">d-</span>Ala2, <span style="font-variant: small-caps;">d</span>-Leu5]-enkephalin (DADLE) reduced the effect of hypoxia on force (recovery to 78 ± 5% of baseline with DADLE preconditioning vs. 57 ± 5% without, <i>p</i> = 0.012), apoptosis and cardiomyocyte stress. Human EHTs presented a comparable hypoxia-induced reduction in force (55 ± 5% of baseline), but DADLE failed to precondition them, likely due to the absence of δ-opioid receptors. In summary, this hypoxia-reoxygenation in vitro model displays cellular damage and the decline of contractile function after hypoxia allows the investigation of preconditioning strategies and will therefore help us to understand the discrepancy between successful conditioning in vitro experiments and its failure in clinical trials. |
| first_indexed | 2024-03-10T16:24:56Z |
| format | Article |
| id | doaj.art-e0b3e8886c6e422aab5e125231a682ab |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T16:24:56Z |
| publishDate | 2020-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-e0b3e8886c6e422aab5e125231a682ab2023-11-20T13:21:27ZengMDPI AGBiomolecules2218-273X2020-09-01109130910.3390/biom10091309Effects of the Delta Opioid Receptor Agonist DADLE in a Novel Hypoxia-Reoxygenation Model on Human and Rat-Engineered Heart Tissue: A Pilot StudySandra Funcke0Tessa R. Werner1Marc Hein2Bärbel M. Ulmer3Arne Hansen4Thomas Eschenhagen5Marc N. Hirt6Department of Anaesthesiology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, GermanyDepartment of Anaesthesiology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, GermanyAnaesthesiology Clinic, RWTH Aachen University, 52074 Aachen, GermanyDepartment of Anaesthesiology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, GermanyDepartment of Anaesthesiology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, GermanyDepartment of Anaesthesiology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, GermanyDepartment of Anaesthesiology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, GermanyIntermittent hypoxia and various pharmacological compounds protect the heart from ischemia reperfusion injury in experimental approaches, but the translation into clinical trials has largely failed. One reason may lie in species differences and the lack of suitable human in vitro models to test for ischemia/reperfusion. We aimed to develop a novel hypoxia-reoxygenation model based on three-dimensional, spontaneously beating and work performing engineered heart tissue (EHT) from rat and human cardiomyocytes. Contractile force, the most important cardiac performance parameter, served as an integrated outcome measure. EHTs from neonatal rat cardiomyocytes were subjected to 90 min of hypoxia which led to cardiomyocyte apoptosis as revealed by caspase 3-staining, increased troponin I release (time control vs. 24 h after hypoxia: cTnI 2.7 vs. 6.3 ng/mL, ** <i>p</i> = 0.002) and decreased contractile force (64 ± 6% of baseline) in the long-term follow-up. The detrimental effects were attenuated by preceding the long-term hypoxia with three cycles of 10 min hypoxia (i.e., hypoxic preconditioning). Similarly, [<span style="font-variant: small-caps;">d-</span>Ala2, <span style="font-variant: small-caps;">d</span>-Leu5]-enkephalin (DADLE) reduced the effect of hypoxia on force (recovery to 78 ± 5% of baseline with DADLE preconditioning vs. 57 ± 5% without, <i>p</i> = 0.012), apoptosis and cardiomyocyte stress. Human EHTs presented a comparable hypoxia-induced reduction in force (55 ± 5% of baseline), but DADLE failed to precondition them, likely due to the absence of δ-opioid receptors. In summary, this hypoxia-reoxygenation in vitro model displays cellular damage and the decline of contractile function after hypoxia allows the investigation of preconditioning strategies and will therefore help us to understand the discrepancy between successful conditioning in vitro experiments and its failure in clinical trials.https://www.mdpi.com/2218-273X/10/9/13093D tissue modelopioidspreconditioningtranslational medicinecardioprotectioncardiac hypertrophy |
| spellingShingle | Sandra Funcke Tessa R. Werner Marc Hein Bärbel M. Ulmer Arne Hansen Thomas Eschenhagen Marc N. Hirt Effects of the Delta Opioid Receptor Agonist DADLE in a Novel Hypoxia-Reoxygenation Model on Human and Rat-Engineered Heart Tissue: A Pilot Study Biomolecules 3D tissue model opioids preconditioning translational medicine cardioprotection cardiac hypertrophy |
| title | Effects of the Delta Opioid Receptor Agonist DADLE in a Novel Hypoxia-Reoxygenation Model on Human and Rat-Engineered Heart Tissue: A Pilot Study |
| title_full | Effects of the Delta Opioid Receptor Agonist DADLE in a Novel Hypoxia-Reoxygenation Model on Human and Rat-Engineered Heart Tissue: A Pilot Study |
| title_fullStr | Effects of the Delta Opioid Receptor Agonist DADLE in a Novel Hypoxia-Reoxygenation Model on Human and Rat-Engineered Heart Tissue: A Pilot Study |
| title_full_unstemmed | Effects of the Delta Opioid Receptor Agonist DADLE in a Novel Hypoxia-Reoxygenation Model on Human and Rat-Engineered Heart Tissue: A Pilot Study |
| title_short | Effects of the Delta Opioid Receptor Agonist DADLE in a Novel Hypoxia-Reoxygenation Model on Human and Rat-Engineered Heart Tissue: A Pilot Study |
| title_sort | effects of the delta opioid receptor agonist dadle in a novel hypoxia reoxygenation model on human and rat engineered heart tissue a pilot study |
| topic | 3D tissue model opioids preconditioning translational medicine cardioprotection cardiac hypertrophy |
| url | https://www.mdpi.com/2218-273X/10/9/1309 |
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