The FXYD1 protein plays a protective role against pulmonary hypertension and arterial remodelling via redox and inflammatory mechanisms.

Abstract

Background: Pulmonary hypertension (PH) consists of a heterogenous group of diseases that culminate in increased pulmonary arterial pressure and right ventricular (RV) dysfunction. We sought to investigate the role of FXYD1, a small membrane protein that modulates Na+-K+-ATPase function, in the pathophysiology of PH. Methods: We mined online transcriptome databases to assess FXYD1 expression in PH. We characterized the effects of FXYD1 knock out (KO) in mice on right and left ventricular (RV and LV) function using echocardiography and measured invasive hemodynamic measurements under normal conditions and after treatment with bleomycin sulfate or chronic hypoxia to induce PH. Using immunohistochemistry, immunoblotting and functional assays, we examined the effects of FXYD1 KO on pulmonary microvasculature and RV and LV structure, and assessed signalling via endothelial nitric oxide synthase (eNOS) and inflammatory pathways. Results: FXYD1 lung expression tended to be lower in samples from patients with IPAH compared with controls, supporting a potential pathophysiological role. FXYD1 KO mice displayed characteristics of PH including significant increases in pulmonary arterial pressure, increased muscularization of small pulmonary arterioles and impaired RV systolic function, in addition to LV systolic dysfunction. However, when PH was stimulated with standard models of lung injury-induced PH, there was no exacerbation of disease in FXYD1 KO mice. Both the lungs and left ventricles exhibited elevated nitrosative stress and inflammatory milieu. Conclusions: The absence of FXYD1 in mice results in LV inflammation and cardiopulmonary redox signaling changes that predispose to pathophysiological features of PH, suggesting FXYD1 may be protective.