α7 Nicotinic acetylcholine receptor mediates right ventricular fibrosis and diastolic dysfunction in pulmonary hypertension
| Autor: | Iuliia Polina, Alexander Vang, Edward Hawrot, Denielli da Silva Gonçalves Bos, Thomas Mancini, Peng Zhang, Michael W. Cypress, Richard T. Clements, Ulrike Mende, Alan R. Morrison, Gaurav Choudhary, Ana Fernandez-Nicolas, Jin O-Uchi, Bong Sook Jhun |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male Pulmonology alpha7 Nicotinic Acetylcholine Receptor Heart Ventricles Hypertension Pulmonary Diastole Cardiology Heart failure Pharmacology Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Afterload Fibrosis medicine Animals Humans Fibroblast Pressure overload business.industry General Medicine medicine.disease Pulmonary hypertension Rats 030104 developmental biology medicine.anatomical_structure HEK293 Cells Ventricle 030220 oncology & carcinogenesis Ion channels Ventricular Function Right Female business Research Article |
| Zdroj: | JCI Insight |
| ISSN: | 2379-3708 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|