Pulmonary Hypertension-Associated Right Ventricular Cardiomyocyte Remodelling Reduces Treprostinil Function
(1) Pulmonary hypertension (PH)-associated right ventricular (RV) failure is linked to a reduction in pulmonary vasodilators. Treprostinil has shown effectiveness in PAH patients with cardiac decompensation, hinting at potential cardiac benefits. We investigated treprostinil’s synergy with isoprenal...
| Principais autores: | , , , , , , , , |
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| Formato: | Artigo |
| Idioma: | English |
| Publicado em: |
MDPI AG
2023-12-01
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| coleção: | Cells |
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| Acesso em linha: | https://www.mdpi.com/2073-4409/12/23/2764 |
| _version_ | 1827592419031384064 |
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| author | Aleksandra Judina Marili Niglas Vladislav Leonov Nicholas S. Kirkby Ivan Diakonov Peter T. Wright Lan Zhao Jane A. Mitchell Julia Gorelik |
| author_facet | Aleksandra Judina Marili Niglas Vladislav Leonov Nicholas S. Kirkby Ivan Diakonov Peter T. Wright Lan Zhao Jane A. Mitchell Julia Gorelik |
| author_sort | Aleksandra Judina |
| collection | DOAJ |
| description | (1) Pulmonary hypertension (PH)-associated right ventricular (RV) failure is linked to a reduction in pulmonary vasodilators. Treprostinil has shown effectiveness in PAH patients with cardiac decompensation, hinting at potential cardiac benefits. We investigated treprostinil’s synergy with isoprenaline in RV and LV cardiomyocytes. We hypothesised that disease-related RV structural changes in cardiomyocytes would reduce contractile responses and cAMP/PKA signalling activity. (2) We induced PH in male Sprague Dawley rats using monocrotaline and isolated their ventricular cardiomyocytes. The effect of in vitro treprostinil and isoprenaline stimulation on contraction was assessed. FRET microscopy was used to study PKA activity associated with treprostinil stimulation in AKAR3-NES FRET-based biosensor-expressing cells. (3) RV cells exhibited maladaptive remodelling with hypertrophy, impaired contractility, and calcium transients compared to control and LV cardiomyocytes. Combining treprostinil and isoprenaline failed to enhance inotropy in PH RV cardiomyocytes. PH RV cardiomyocytes displayed an aberrant contractile behaviour, which the combination treatment could not rectify. Finally, we observed decreased PKA activity in treprostinil-treated PH RV cardiomyocytes. (4) PH-associated RV cardiomyocyte remodelling reduced treprostinil sensitivity, inotropic support, and impaired relaxation. Overall, this study highlights the complexity of RV dysfunction in advanced PH and suggests the need for alternative therapeutic strategies. |
| first_indexed | 2024-03-09T01:54:15Z |
| format | Article |
| id | doaj.art-d9c9e0ef31eb4ac383dcf8f7feb383b1 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T01:54:15Z |
| publishDate | 2023-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-d9c9e0ef31eb4ac383dcf8f7feb383b12023-12-08T15:13:17ZengMDPI AGCells2073-44092023-12-011223276410.3390/cells12232764Pulmonary Hypertension-Associated Right Ventricular Cardiomyocyte Remodelling Reduces Treprostinil FunctionAleksandra Judina0Marili Niglas1Vladislav Leonov2Nicholas S. Kirkby3Ivan Diakonov4Peter T. Wright5Lan Zhao6Jane A. Mitchell7Julia Gorelik8Cardiac Section, National Heart and Lung Institute (NHLI), Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UKCardiac Section, National Heart and Lung Institute (NHLI), Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UKCardiac Section, National Heart and Lung Institute (NHLI), Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UKCardiac Section, National Heart and Lung Institute (NHLI), Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UKCardiac Section, National Heart and Lung Institute (NHLI), Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UKDefinitely School of Life and Health Sciences, Whitelands College, University of Roehampton, Holybourne Avenue, London SW15 4JD, UKCardiac Section, National Heart and Lung Institute (NHLI), Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UKCardiac Section, National Heart and Lung Institute (NHLI), Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UKCardiac Section, National Heart and Lung Institute (NHLI), Faculty of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK(1) Pulmonary hypertension (PH)-associated right ventricular (RV) failure is linked to a reduction in pulmonary vasodilators. Treprostinil has shown effectiveness in PAH patients with cardiac decompensation, hinting at potential cardiac benefits. We investigated treprostinil’s synergy with isoprenaline in RV and LV cardiomyocytes. We hypothesised that disease-related RV structural changes in cardiomyocytes would reduce contractile responses and cAMP/PKA signalling activity. (2) We induced PH in male Sprague Dawley rats using monocrotaline and isolated their ventricular cardiomyocytes. The effect of in vitro treprostinil and isoprenaline stimulation on contraction was assessed. FRET microscopy was used to study PKA activity associated with treprostinil stimulation in AKAR3-NES FRET-based biosensor-expressing cells. (3) RV cells exhibited maladaptive remodelling with hypertrophy, impaired contractility, and calcium transients compared to control and LV cardiomyocytes. Combining treprostinil and isoprenaline failed to enhance inotropy in PH RV cardiomyocytes. PH RV cardiomyocytes displayed an aberrant contractile behaviour, which the combination treatment could not rectify. Finally, we observed decreased PKA activity in treprostinil-treated PH RV cardiomyocytes. (4) PH-associated RV cardiomyocyte remodelling reduced treprostinil sensitivity, inotropic support, and impaired relaxation. Overall, this study highlights the complexity of RV dysfunction in advanced PH and suggests the need for alternative therapeutic strategies.https://www.mdpi.com/2073-4409/12/23/2764pulmonary hypertensionright ventriclecardiomyocytestreprostinilsarcomere shorteningcell length deflection |
| spellingShingle | Aleksandra Judina Marili Niglas Vladislav Leonov Nicholas S. Kirkby Ivan Diakonov Peter T. Wright Lan Zhao Jane A. Mitchell Julia Gorelik Pulmonary Hypertension-Associated Right Ventricular Cardiomyocyte Remodelling Reduces Treprostinil Function Cells pulmonary hypertension right ventricle cardiomyocytes treprostinil sarcomere shortening cell length deflection |
| title | Pulmonary Hypertension-Associated Right Ventricular Cardiomyocyte Remodelling Reduces Treprostinil Function |
| title_full | Pulmonary Hypertension-Associated Right Ventricular Cardiomyocyte Remodelling Reduces Treprostinil Function |
| title_fullStr | Pulmonary Hypertension-Associated Right Ventricular Cardiomyocyte Remodelling Reduces Treprostinil Function |
| title_full_unstemmed | Pulmonary Hypertension-Associated Right Ventricular Cardiomyocyte Remodelling Reduces Treprostinil Function |
| title_short | Pulmonary Hypertension-Associated Right Ventricular Cardiomyocyte Remodelling Reduces Treprostinil Function |
| title_sort | pulmonary hypertension associated right ventricular cardiomyocyte remodelling reduces treprostinil function |
| topic | pulmonary hypertension right ventricle cardiomyocytes treprostinil sarcomere shortening cell length deflection |
| url | https://www.mdpi.com/2073-4409/12/23/2764 |
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