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

Ulrike Mende,Jin O-Uchi,Ana Fernandez-Nicolas,Alexander Vang,Richard T. Clements,Alan R. Morrison,Iuliia Polina,Edward Hawrot,Bong Sook Jhun,Gaurav Choudhary,Michael W. Cypress,Thomas J. Mancini,Denielli da Silva Gonçalves Bos,Peng Zhang

doi:10.1172/jci.insight.142945

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 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.

Highlights

Myocardial fibrosis is a process of pathological extracellular matrix (ECM) remodeling, mediated by activation of cardiac fibroblasts (CFs) [1,2,3]
In order to assess the role of α7 nAChR signaling in right ventricular (RV) fibrosis and dysfunction, we studied a rat pulmonary hypertension (PH) model at 2 time points (3 and 7 weeks, Figure 1A) that develops severe PH (Figure 1B) with increased RV end diastolic pressure (Figure 1C), RV hypertrophy (Figure 1D), RV systolic and diastolic dysfunction (Figure 1, E and F, respectively), and reduced cardiac output (Figure 1G) in response to SU5416/hypoxia (SuHx) [8, 26]
While α7 nAChR was predominantly expressed in the CF, overall expression of nAChR remained unaltered in isolated right ventricular cardiac fibroblast (RVCF) from PH rats compared with controls at the 7-week time point (Figure 2D)

Summary

Introduction

Myocardial fibrosis is a process of pathological extracellular matrix (ECM) remodeling, mediated by activation of cardiac fibroblasts (CFs) [1,2,3]. Mechanisms of increased cardiac fibrosis and fibroblast proliferation/transformation have predominantly been studied in the left ventricle (LV). They include TGF-β signaling, the renin-angiotensinaldosterone system signaling, adrenergic and endothelin G-protein–coupled receptor signaling, growth factor–mediated tyrosine kinase signaling, and a number of other inflammatory-based pathways [1, 4]. Far less is known about the mechanisms driving right ventricular (RV) fibrosis [5,6,7]. This is notable since we and others have demonstrated that some established therapies targeting LV fibrosis, such as angiotensin receptor antagonism, do not attenuate RV fibrosis [8, 9]

Methods

Results

Conclusion