Endothelin Receptor Autoantibodies as Emerging Biomarkers and Therapeutic Targets in the Cardiovascular Complications of Lupus

Patients with systemic lupus erythematosus (SLE) are at increased risk of hypertension (HTN) and cardiovascular disease, yet the immunologic drivers of this endothelial and vascular dysfunction remain incompletely understood. Here, we investigate whether autoantibodies targeting endothelin receptors are associated with an SLE diagnosis, elevated blood pressure, and endothelial activation. In two independent clinical cohorts (n = 214), we quantified anti-endothelin receptor A (ET_AR) and endothelin receptor B (ET_BR) autoantibodies and additionally quantified soluble vascular adhesion molecule-1 (sVCAM-1) and intracellular adhesion molecule-1 (sICAM-1) as markers of endothelial activation. In both independent cohorts, we report significantly elevated anti-ET_AR autoantibodies, anti-ET_BR autoantibodies, and sVCAM-1 in individuals with SLE compared to controls. Anti-ET_AR autoantibodies, Anti-ET_BR autoantibodies, and sVCAM-1 levels were significantly increased in SLE subjects independent of HTN status. Anti-ET_AR autoantibodies correlated positively with systolic and diastolic blood pressure, sVCAM-1, sICAM-1, and anti-ET_BR autoantibodies. These findings identify a novel immunological signature of endothelial dysfunction in SLE and implicate anti-endothelin receptor autoantibodies as potential biomarkers and therapeutic targets in SLE and its associated HTN.