Alpha 7 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 fibroblast alpha 7 nicotinic acetylcholine receptor (alpha 7 nAChR) drives smoking-induced RV fibrosis. Here, we sought to define the role of alpha 7 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 alpha 7 nAChR expression in the RV but not in the left ventricle (LV). In vitro studies show that alpha 7 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 alpha 7 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 alpha 7 nAChR signaling is an important mechanism underlying RV fibrosis and dysfunction, and targeted inhibition of alpha 7 nAChR is a potentially novel therapeutic strategy in the setting of increased RV afterload.