α7 Nicotinic acetylcholine receptor mediates right ventricular fibrosis and diastolic dysfunction in pulmonary hypertension

Abstract

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 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 LV. In vitro studies show that α7 nAChR activation leads to an increase in adult ventricular fibroblast proliferation and collagen content mediated by a Ca 2+ / epidermal growth factor receptor (EGFR) signaling mechanism. Pharmacological antagonism of nAChR decreases RV collagen content and improves RV function in the PH model. Further, mice lacking α7 nAChR exhibit improved RV diastolic function and have lower RV collagen content in response to persistently increased RV afterload, compared to wild-type 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 novel therapeutic strategy in the setting of increased RV afterload.

Diminished α7 nicotinic acetylcholine receptor (α7nAChR) rescues amyloid-β induced atrial remodeling by oxi-CaMKII/MAPK/AP-1 axis-mediated mitochondrial oxidative stress

“…α7nAChR has made a lot of progress in the research related to the improvement of cognitive function, and therapeutic effects of α7nAChR agonists on AD have been widely reported [ 41 ]. However, it has been reported that the activation of α7nAChR can promote the formation of fibrosis, atherosclerosis and right ventricular dysfunction [ 42 , 43 ]. Hence one can see that α7nAChR plays various, even contrary, functions on different types of cells and diseases.…”

Urokinase-loaded cyclic RGD-decorated liposome targeted therapy for in-situ thrombus of pulmonary arteriole of pulmonary hypertension

“…MCT-induced PH belongs to PAH (Group 1); in PAH patients, improvement in RV function was critical to lowering mortality ( Potus et al, 2015 ; Clapham et al, 2020 ). PAH induces an increase in RV afterload, which eventually results in fibrosis of RV myocardial tissue and RV dysfunction when the afterload exceeds RV compensatory capacity ( Vang et al, 2021 ). In our study, rats in the UK-cRGD-LIP group had considerably improved RV systolic function and RV pumping efficiency ( Figures 9B,E–G ) post targeted thrombolytic therapy.…”

Nicotine and novel tobacco products drive adverse cardiac remodeling and dysfunction in preclinical studies

“…Nicotine-induced pulmonary hypertension, RV remodeling, and vascular dysfunction are ameliorated by α7 nicotinic cholinergic receptor knockout, and are absent in female mice ( 58 ). The pathogenesis of pulmonary hypertension induced by Sugen and hypoxia also involves α7 nicotinic cholinergic receptor-mediated cross-talk between cardiomyocytes and cardiac fibroblasts, leading to RV fibrosis ( 60 ). Treatment of cardiac fibroblasts isolated from the RV, but not the LV, with cigarette smoke extracts or 600 nM of nicotine stimulated fibroblast proliferation ( 61 ).…”