Activation of α7nAChR prevents maladaptive right ventricular remodeling via inhibiting the recruitment of CCR2+ macrophages in experimental pulmonary arterial hypertension

The transition from adaptive to maladaptive right ventricular (RV) remodeling leads to RV failure (RVF), which is the strongest predictor of mortality in pulmonary arterial hypertension (PAH). However, effective treatments for PAH RVF are currently lacking. Recent studies have implicated C–C chemokine receptor type 2 (CCR2)+ macrophages in promoting PAH RVF. Stimulation of α7 nicotinic acetylcholine receptors (α7nAChR) expressed on macrophages regulates local and systemic inflammation. This study aimed to evaluate the effects of α7nAChR activation on RV remodeling and inflammation in PAH. Monocrotaline (MCT)-induced PAH rats were used to mimic the continuum of RV remodeling. The dynamics of RV CCR2+ macrophages, CD43lowHis48high monocytes and inflammatory genes expression were investigated by immunostaining, flow cytometry and real-time polymerase chain reaction. MCT rats were treated with the selective α7nAChR agonist PNU-282987 or the antagonist methyllycaconitine consecutively for 4 weeks, starting 1 week after MCT injection. Echocardiography, hemodynamics and RV pathology were assessed. The abundance, functional phenotype and C–C chemokine ligand 2 (CCL2) secretion of RV CCR2+ macrophages were evaluated. In vitro activation of α7nAChR was performed on bone-marrow derived macrophages. Increased infiltration of RV CCR2+ macrophages and CD43lowHis48high monocytes, and elevated inflammatory gene expression were associated with maladaptive RV remodeling in PAH rats. In vivo, PNU-282987 reduced mortality, prevented maladaptive RV remodeling, and restored RV function. Furthermore, PNU-282987 inhibited the recruitment of RV CCR2+ macrophages by suppressing the CCL2-CCR2 chemotactic axis and enhanced the anti-inflammatory phenotype of RV CCR2+ macrophages. In vitro experiments confirmed these effects of PNU-282987 on CCR2+ macrophages. Activation of α7nAChR prevents PAH-induced maladaptive RV remodeling by inhibiting the recruitment of CCR2+ macrophages, thereby offering a novel therapeutic strategy for PAH RVF.