Anti-Endothelin Receptor Type A Autoantibodies in Systemic Lupus Erythematosus-Associated Pulmonary Arterial Hypertension

Objective. To investigate the role of autoantibodies against endothelin 1 receptor type A (ETRA) in patients with systemic lupus erythematosus (SLE)-associated pulmonary arterial hypertension (PAH) and to examine the possibility that the pathogenesis of this disease is mediated by these autoantibodies. Methods. ETRA autoantibodies in serum from patients with SLE-associated PAH and serum from controls (SLE patients without PAH) were detected via a human ETRA epitope peptide-based enzyme-linked immunosorbent assay. An exploratory cohort of patients with SLE-associated PAH (n=76) and an independent validation cohort of patients with SLE-associated PAH confirmed by right-sided heart catheterization (RHC) (n=82) were enrolled. The clinical relevance of ETRA autoantibodies in SLE-associated PAH was analyzed. The proliferation of vascular smooth muscle cells (SMCs) and the permeability of endothelial cells (ECs) were assessed in vitro in cells stimulated with polyclonal ETRA IgG autoantibodies. Expression of PAH-related markers, i.e., serotonin transporter, platelet-derived growth factor receptor , vascular endothelial growth factor A, and platelet-derived growth factor B was measured by quantitative polymerase chain reaction. In addition, a suboptimal dose of monocrotaline was used to induce PAH in rats, and the effect of ETRA autoantibodies in vivo was determined using a right ventricular hypertrophy index, pulmonary angiography, and laboratory parameters. Results. ETRA autoantibodies occurred more frequently in SLE-associated PAH (41.5%) than in controls (17.1%). There was a significant correlation between ETRA autoantibody titers and pulmonary artery systolic pressure measured by echocardiography (r=0.2978, P=0.0038) or pulmonary artery systolic pressure measured by RHC (r=0.2159, P=0.0257) in SLE-associated PAH. ETRA autoantibodies could promote SMC proliferation, disrupt the endothelial barrier, and up-regulate expression of PAH-related markers, which could be blocked in the presence of an endothelin receptor antagonist. ETRA autoantibodies aggravated right ventricular hypertrophy and vascular remodeling in vivo. Conclusion. We identified ETRA autoantibodies as a biomarker of mechanistic relevance in SLE. These autoantibodies may mediate PAH development in SLE.