Direct Delivery of MicroRNA96 to the Lungs Reduces Progression of Sugen/Hypoxia-Induced Pulmonary Hypertension in the Rat
The 5HT1B receptor (5HT1BR) contributes to the pathogenic effects of serotonin in pulmonary arterial hypertension. Here, we determine the effect of a microRNA96 (miR96) mimic delivered directly to the lungs on development of severe pulmonary hypertension in rats. Female rats were dosed with sugen (3...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-12-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253120302730 |
| _version_ | 1818648121184354304 |
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| author | Craig K. Docherty Nina Denver Simon Fisher Margaret Nilsen Dianne Hillyard Rebecca L. Openshaw Hicham Labazi Margaret R. MacLean |
| author_facet | Craig K. Docherty Nina Denver Simon Fisher Margaret Nilsen Dianne Hillyard Rebecca L. Openshaw Hicham Labazi Margaret R. MacLean |
| author_sort | Craig K. Docherty |
| collection | DOAJ |
| description | The 5HT1B receptor (5HT1BR) contributes to the pathogenic effects of serotonin in pulmonary arterial hypertension. Here, we determine the effect of a microRNA96 (miR96) mimic delivered directly to the lungs on development of severe pulmonary hypertension in rats. Female rats were dosed with sugen (30 mg/kg) and subjected to 3 weeks of hypobaric hypoxia. In normoxia, rats were dosed with either a 5HT1BR antagonist SB216641 (7.5 mg/kg/day for 3 weeks), miR96, or scramble sequence (50 μg per rat), delivered by intratracheal (i.t) administration, once a week for 3 weeks. Cardiac hemodynamics were determined, pulmonary vascular remodeling was assessed, and gene expression was assessed by qRT-PCR, and in situ hybridization and protein expression were assessed by western blot and ELISA. miR96 expression was increased in pulmonary arteries and associated with a downregulation of the 5HT1BR protein in the lung. miR96 reduced progression of right ventricular systolic pressure, pulmonary arterial remodeling, right ventricular hypertrophy, and the occurrence of occlusive pulmonary lesions. Importantly, miR96 had no off-target effects and did not affect fibrotic markers of liver and kidney function. In conclusion, direct delivery of miR96 to the lungs was effective, reducing progression of sugen/hypoxia-induced pulmonary hypertension with no measured off-target effects. miR96 may be a novel therapy for pulmonary arterial hypertension, acting through downregulation of 5HT1BR. |
| first_indexed | 2024-12-17T01:13:23Z |
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| id | doaj.art-e5d263e8dc1b4639b7c47108893f55bc |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-12-17T01:13:23Z |
| publishDate | 2020-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-e5d263e8dc1b4639b7c47108893f55bc2022-12-21T22:09:06ZengElsevierMolecular Therapy: Nucleic Acids2162-25312020-12-0122396405Direct Delivery of MicroRNA96 to the Lungs Reduces Progression of Sugen/Hypoxia-Induced Pulmonary Hypertension in the RatCraig K. Docherty0Nina Denver1Simon Fisher2Margaret Nilsen3Dianne Hillyard4Rebecca L. Openshaw5Hicham Labazi6Margaret R. MacLean7Strathclyde Institute of Pharmacy and Biological Sciences, University of Strathclyde, Glasgow G4 0RE, Scotland; Institute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, ScotlandStrathclyde Institute of Pharmacy and Biological Sciences, University of Strathclyde, Glasgow G4 0RE, ScotlandInstitute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, ScotlandStrathclyde Institute of Pharmacy and Biological Sciences, University of Strathclyde, Glasgow G4 0RE, Scotland; Institute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, ScotlandInstitute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, ScotlandStrathclyde Institute of Pharmacy and Biological Sciences, University of Strathclyde, Glasgow G4 0RE, ScotlandStrathclyde Institute of Pharmacy and Biological Sciences, University of Strathclyde, Glasgow G4 0RE, ScotlandStrathclyde Institute of Pharmacy and Biological Sciences, University of Strathclyde, Glasgow G4 0RE, Scotland; Institute of Cardiovascular and Medical Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, Scotland; Corresponding author: Margaret R. MacLean, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, HW406, The Hamnett Wing, 161 Cathedral Street, Glasgow G4 0RE, Scotland.The 5HT1B receptor (5HT1BR) contributes to the pathogenic effects of serotonin in pulmonary arterial hypertension. Here, we determine the effect of a microRNA96 (miR96) mimic delivered directly to the lungs on development of severe pulmonary hypertension in rats. Female rats were dosed with sugen (30 mg/kg) and subjected to 3 weeks of hypobaric hypoxia. In normoxia, rats were dosed with either a 5HT1BR antagonist SB216641 (7.5 mg/kg/day for 3 weeks), miR96, or scramble sequence (50 μg per rat), delivered by intratracheal (i.t) administration, once a week for 3 weeks. Cardiac hemodynamics were determined, pulmonary vascular remodeling was assessed, and gene expression was assessed by qRT-PCR, and in situ hybridization and protein expression were assessed by western blot and ELISA. miR96 expression was increased in pulmonary arteries and associated with a downregulation of the 5HT1BR protein in the lung. miR96 reduced progression of right ventricular systolic pressure, pulmonary arterial remodeling, right ventricular hypertrophy, and the occurrence of occlusive pulmonary lesions. Importantly, miR96 had no off-target effects and did not affect fibrotic markers of liver and kidney function. In conclusion, direct delivery of miR96 to the lungs was effective, reducing progression of sugen/hypoxia-induced pulmonary hypertension with no measured off-target effects. miR96 may be a novel therapy for pulmonary arterial hypertension, acting through downregulation of 5HT1BR.http://www.sciencedirect.com/science/article/pii/S2162253120302730pulmonary hypertensionserotoninmicroRNA96 |
| spellingShingle | Craig K. Docherty Nina Denver Simon Fisher Margaret Nilsen Dianne Hillyard Rebecca L. Openshaw Hicham Labazi Margaret R. MacLean Direct Delivery of MicroRNA96 to the Lungs Reduces Progression of Sugen/Hypoxia-Induced Pulmonary Hypertension in the Rat Molecular Therapy: Nucleic Acids pulmonary hypertension serotonin microRNA96 |
| title | Direct Delivery of MicroRNA96 to the Lungs Reduces Progression of Sugen/Hypoxia-Induced Pulmonary Hypertension in the Rat |
| title_full | Direct Delivery of MicroRNA96 to the Lungs Reduces Progression of Sugen/Hypoxia-Induced Pulmonary Hypertension in the Rat |
| title_fullStr | Direct Delivery of MicroRNA96 to the Lungs Reduces Progression of Sugen/Hypoxia-Induced Pulmonary Hypertension in the Rat |
| title_full_unstemmed | Direct Delivery of MicroRNA96 to the Lungs Reduces Progression of Sugen/Hypoxia-Induced Pulmonary Hypertension in the Rat |
| title_short | Direct Delivery of MicroRNA96 to the Lungs Reduces Progression of Sugen/Hypoxia-Induced Pulmonary Hypertension in the Rat |
| title_sort | direct delivery of microrna96 to the lungs reduces progression of sugen hypoxia induced pulmonary hypertension in the rat |
| topic | pulmonary hypertension serotonin microRNA96 |
| url | http://www.sciencedirect.com/science/article/pii/S2162253120302730 |
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