α7 Nicotinic acetylcholine receptor mediates right ventricular fibrosis and diastolic dysfunction in pulmonary hypertension
Right ventricular (RV) fibrosis is a key feature of maladaptive RV hypertrophy and dysfunction and is associated with poor outcomes in pulmonary hypertension (PH). However, mechanisms and therapeutic strategies to mitigate RV fibrosis remain unrealized. Previously, we identified that cardiac fibrobl...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical investigation
2021-06-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.142945 |
| _version_ | 1811329104912318464 |
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| author | Alexander Vang Denielli da Silva Gonçalves Bos Ana Fernandez-Nicolas Peng Zhang Alan R. Morrison Thomas J. Mancini Richard T. Clements Iuliia Polina Michael W. Cypress Bong Sook Jhun Edward Hawrot Ulrike Mende Jin O-Uchi Gaurav Choudhary |
| author_facet | Alexander Vang Denielli da Silva Gonçalves Bos Ana Fernandez-Nicolas Peng Zhang Alan R. Morrison Thomas J. Mancini Richard T. Clements Iuliia Polina Michael W. Cypress Bong Sook Jhun Edward Hawrot Ulrike Mende Jin O-Uchi Gaurav Choudhary |
| author_sort | Alexander Vang |
| collection | DOAJ |
| description | Right ventricular (RV) fibrosis is a key feature of maladaptive RV hypertrophy and dysfunction and is associated with poor outcomes in pulmonary hypertension (PH). However, mechanisms and therapeutic strategies to mitigate RV fibrosis remain unrealized. Previously, we identified that cardiac fibroblast α7 nicotinic acetylcholine receptor (α7 nAChR) drives smoking-induced RV fibrosis. Here, we sought to define the role of α7 nAChR in RV dysfunction and fibrosis in the settings of RV pressure overload as seen in PH. We show that RV tissue from PH patients has increased collagen content and ACh expression. Using an experimental rat model of PH, we demonstrate that RV fibrosis and dysfunction are associated with increases in ACh and α7 nAChR expression in the RV but not in the left ventricle (LV). In vitro studies show that α7 nAChR activation leads to an increase in adult ventricular fibroblast proliferation and collagen content mediated by a Ca2+/epidermal growth factor receptor (EGFR) signaling mechanism. Pharmacological antagonism of nAChR decreases RV collagen content and improves RV function in the PH model. Furthermore, mice lacking α7 nAChR exhibit improved RV diastolic function and have lower RV collagen content in response to persistently increased RV afterload, compared with WT controls. These finding indicate that enhanced α7 nAChR signaling is an important mechanism underlying RV fibrosis and dysfunction, and targeted inhibition of α7 nAChR is a potentially novel therapeutic strategy in the setting of increased RV afterload. |
| first_indexed | 2024-04-13T15:38:00Z |
| format | Article |
| id | doaj.art-c09c89c74fdf402a92c4c34005193f3d |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-04-13T15:38:00Z |
| publishDate | 2021-06-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-c09c89c74fdf402a92c4c34005193f3d2022-12-22T02:41:13ZengAmerican Society for Clinical investigationJCI Insight2379-37082021-06-01612α7 Nicotinic acetylcholine receptor mediates right ventricular fibrosis and diastolic dysfunction in pulmonary hypertensionAlexander VangDenielli da Silva Gonçalves BosAna Fernandez-NicolasPeng ZhangAlan R. MorrisonThomas J. ManciniRichard T. ClementsIuliia PolinaMichael W. CypressBong Sook JhunEdward HawrotUlrike MendeJin O-UchiGaurav ChoudharyRight ventricular (RV) fibrosis is a key feature of maladaptive RV hypertrophy and dysfunction and is associated with poor outcomes in pulmonary hypertension (PH). However, mechanisms and therapeutic strategies to mitigate RV fibrosis remain unrealized. Previously, we identified that cardiac fibroblast α7 nicotinic acetylcholine receptor (α7 nAChR) drives smoking-induced RV fibrosis. Here, we sought to define the role of α7 nAChR in RV dysfunction and fibrosis in the settings of RV pressure overload as seen in PH. We show that RV tissue from PH patients has increased collagen content and ACh expression. Using an experimental rat model of PH, we demonstrate that RV fibrosis and dysfunction are associated with increases in ACh and α7 nAChR expression in the RV but not in the left ventricle (LV). In vitro studies show that α7 nAChR activation leads to an increase in adult ventricular fibroblast proliferation and collagen content mediated by a Ca2+/epidermal growth factor receptor (EGFR) signaling mechanism. Pharmacological antagonism of nAChR decreases RV collagen content and improves RV function in the PH model. Furthermore, mice lacking α7 nAChR exhibit improved RV diastolic function and have lower RV collagen content in response to persistently increased RV afterload, compared with WT controls. These finding indicate that enhanced α7 nAChR signaling is an important mechanism underlying RV fibrosis and dysfunction, and targeted inhibition of α7 nAChR is a potentially novel therapeutic strategy in the setting of increased RV afterload.https://doi.org/10.1172/jci.insight.142945CardiologyPulmonology |
| spellingShingle | Alexander Vang Denielli da Silva Gonçalves Bos Ana Fernandez-Nicolas Peng Zhang Alan R. Morrison Thomas J. Mancini Richard T. Clements Iuliia Polina Michael W. Cypress Bong Sook Jhun Edward Hawrot Ulrike Mende Jin O-Uchi Gaurav Choudhary α7 Nicotinic acetylcholine receptor mediates right ventricular fibrosis and diastolic dysfunction in pulmonary hypertension JCI Insight Cardiology Pulmonology |
| title | α7 Nicotinic acetylcholine receptor mediates right ventricular fibrosis and diastolic dysfunction in pulmonary hypertension |
| title_full | α7 Nicotinic acetylcholine receptor mediates right ventricular fibrosis and diastolic dysfunction in pulmonary hypertension |
| title_fullStr | α7 Nicotinic acetylcholine receptor mediates right ventricular fibrosis and diastolic dysfunction in pulmonary hypertension |
| title_full_unstemmed | α7 Nicotinic acetylcholine receptor mediates right ventricular fibrosis and diastolic dysfunction in pulmonary hypertension |
| title_short | α7 Nicotinic acetylcholine receptor mediates right ventricular fibrosis and diastolic dysfunction in pulmonary hypertension |
| title_sort | α7 nicotinic acetylcholine receptor mediates right ventricular fibrosis and diastolic dysfunction in pulmonary hypertension |
| topic | Cardiology Pulmonology |
| url | https://doi.org/10.1172/jci.insight.142945 |
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