A Novel Dual-Function Redox Modulator Relieves Oxidative Stress and Anti-Angiogenic Response in Placental Villus Explant Exposed to Hypoxia—Relevance for Preeclampsia Therapy
Background: Preeclampsia (PE) is a severe, life-threatening complication during pregnancy (~5–7%), and no causative treatment is available. Early aberrant spiral artery remodeling is associated with placental stress and the release of oxygen radicals and other reactive oxygen species (ROS) in the pl...
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MDPI AG
2023-09-01
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| Series: | Biology |
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| Online Access: | https://www.mdpi.com/2079-7737/12/9/1229 |
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| author | Diana Pintye Réka E. Sziva Maxim Mastyugin Brett C. Young Sonako Jacas Marianna Török Saira Salahuddin Prakash Jagtap Garry J. Southan Zsuzsanna K. Zsengellér |
| author_facet | Diana Pintye Réka E. Sziva Maxim Mastyugin Brett C. Young Sonako Jacas Marianna Török Saira Salahuddin Prakash Jagtap Garry J. Southan Zsuzsanna K. Zsengellér |
| author_sort | Diana Pintye |
| collection | DOAJ |
| description | Background: Preeclampsia (PE) is a severe, life-threatening complication during pregnancy (~5–7%), and no causative treatment is available. Early aberrant spiral artery remodeling is associated with placental stress and the release of oxygen radicals and other reactive oxygen species (ROS) in the placenta. This precedes the production of anti-angiogenic factors, which ultimately leads to endothelial and trophoblast damage and the key features of PE. We tested whether a novel dual-function redox modulator—AKT-1005—can effectively reduce placental oxidative stress and alleviate PE symptoms in vitro. Method: Isolated human villous explants were exposed to hypoxia and assessed to determine whether improving cell-redox function with AKT-1005 diminished ROS production, mitochondrial stress, production of the transcription factor HIF1A, and downstream anti-angiogenic responses (i.e., sFLT1, sEng production). MitoTEMPO was used as a reference antioxidant. Results: In our villous explant assays, pretreatment with AKT-1005 reduced mitochondrial-derived ROS production, reduced HIF-1A, sFLT1, and sEng protein expression, while increasing VEGF in hypoxia-exposed villous trophoblast cells, with better efficiency than MitoTEMPO. In addition, AKT-1005 improved mitochondrial electron chain enzyme activity in the stressed explant culture. Conclusions: The redox modulator AKT-1005 has the potential to intervene with oxidative stress and can be efficacious for PE therapy. Future studies are underway to assess the in vivo efficacy of HMP. |
| first_indexed | 2024-03-10T23:01:26Z |
| format | Article |
| id | doaj.art-6d4aee7da3784754b6504db4a144336f |
| institution | Directory Open Access Journal |
| issn | 2079-7737 |
| language | English |
| last_indexed | 2024-03-10T23:01:26Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biology |
| spelling | doaj.art-6d4aee7da3784754b6504db4a144336f2023-11-19T09:38:50ZengMDPI AGBiology2079-77372023-09-01129122910.3390/biology12091229A Novel Dual-Function Redox Modulator Relieves Oxidative Stress and Anti-Angiogenic Response in Placental Villus Explant Exposed to Hypoxia—Relevance for Preeclampsia TherapyDiana Pintye0Réka E. Sziva1Maxim Mastyugin2Brett C. Young3Sonako Jacas4Marianna Török5Saira Salahuddin6Prakash Jagtap7Garry J. Southan8Zsuzsanna K. Zsengellér9Department of Medicine, Beth Israel Lahey Health, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USADepartment of Medicine, Beth Israel Lahey Health, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USADepartment of Chemistry, University of Massachusetts, Boston, MA 02125, USADepartment of Obstetrics and Gynecology, Beth Israel Lahey Health, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USADepartment of Medicine, Beth Israel Lahey Health, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USADepartment of Chemistry, University of Massachusetts, Boston, MA 02125, USADepartment of Obstetrics and Gynecology, Beth Israel Lahey Health, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USAAkkadian Therapeutics, Stoneham, MA 02180, USAAkkadian Therapeutics, Stoneham, MA 02180, USADepartment of Medicine, Beth Israel Lahey Health, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USABackground: Preeclampsia (PE) is a severe, life-threatening complication during pregnancy (~5–7%), and no causative treatment is available. Early aberrant spiral artery remodeling is associated with placental stress and the release of oxygen radicals and other reactive oxygen species (ROS) in the placenta. This precedes the production of anti-angiogenic factors, which ultimately leads to endothelial and trophoblast damage and the key features of PE. We tested whether a novel dual-function redox modulator—AKT-1005—can effectively reduce placental oxidative stress and alleviate PE symptoms in vitro. Method: Isolated human villous explants were exposed to hypoxia and assessed to determine whether improving cell-redox function with AKT-1005 diminished ROS production, mitochondrial stress, production of the transcription factor HIF1A, and downstream anti-angiogenic responses (i.e., sFLT1, sEng production). MitoTEMPO was used as a reference antioxidant. Results: In our villous explant assays, pretreatment with AKT-1005 reduced mitochondrial-derived ROS production, reduced HIF-1A, sFLT1, and sEng protein expression, while increasing VEGF in hypoxia-exposed villous trophoblast cells, with better efficiency than MitoTEMPO. In addition, AKT-1005 improved mitochondrial electron chain enzyme activity in the stressed explant culture. Conclusions: The redox modulator AKT-1005 has the potential to intervene with oxidative stress and can be efficacious for PE therapy. Future studies are underway to assess the in vivo efficacy of HMP.https://www.mdpi.com/2079-7737/12/9/1229preeclampsianitric oxide-donorredox modulatorSOD mimeticplacental villous explanthypoxia |
| spellingShingle | Diana Pintye Réka E. Sziva Maxim Mastyugin Brett C. Young Sonako Jacas Marianna Török Saira Salahuddin Prakash Jagtap Garry J. Southan Zsuzsanna K. Zsengellér A Novel Dual-Function Redox Modulator Relieves Oxidative Stress and Anti-Angiogenic Response in Placental Villus Explant Exposed to Hypoxia—Relevance for Preeclampsia Therapy Biology preeclampsia nitric oxide-donor redox modulator SOD mimetic placental villous explant hypoxia |
| title | A Novel Dual-Function Redox Modulator Relieves Oxidative Stress and Anti-Angiogenic Response in Placental Villus Explant Exposed to Hypoxia—Relevance for Preeclampsia Therapy |
| title_full | A Novel Dual-Function Redox Modulator Relieves Oxidative Stress and Anti-Angiogenic Response in Placental Villus Explant Exposed to Hypoxia—Relevance for Preeclampsia Therapy |
| title_fullStr | A Novel Dual-Function Redox Modulator Relieves Oxidative Stress and Anti-Angiogenic Response in Placental Villus Explant Exposed to Hypoxia—Relevance for Preeclampsia Therapy |
| title_full_unstemmed | A Novel Dual-Function Redox Modulator Relieves Oxidative Stress and Anti-Angiogenic Response in Placental Villus Explant Exposed to Hypoxia—Relevance for Preeclampsia Therapy |
| title_short | A Novel Dual-Function Redox Modulator Relieves Oxidative Stress and Anti-Angiogenic Response in Placental Villus Explant Exposed to Hypoxia—Relevance for Preeclampsia Therapy |
| title_sort | novel dual function redox modulator relieves oxidative stress and anti angiogenic response in placental villus explant exposed to hypoxia relevance for preeclampsia therapy |
| topic | preeclampsia nitric oxide-donor redox modulator SOD mimetic placental villous explant hypoxia |
| url | https://www.mdpi.com/2079-7737/12/9/1229 |
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