Endothelin System Dysregulation as a Driver of Cardiovascular Inflammation and Dysfunction in Systemic Lupus Erythematosus

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Endothelial dysfunction is a key contributor to cardiovascular disease (CVD), particularly in hypertension (HTN), the leading risk factor. Patients with systemic lupus erythematosus (SLE), a chronic autoimmune disorder, develop HTN at higher rates than non-SLE individuals, and CVD has recently surpassed infection as the leading cause of mortality in SLE. This study investigates how the potent vasoconstrictor endothelin-1 (ET-1) contributes to SLE-associated CVD in human subjects, the B6.Nba2 murine model of SLE-associated CVD, and primary human renal endothelial cells (HREC). Female and male subjects: Non-SLE Non-HTN (f/m; n=31/15), Non-SLE HTN (n=29/7), SLE Non-HTN (n=34/15), and SLE HTN (n=35/15) were recruited for plasma analysis of ET-1 and endothelial activation via soluble vascular cell adhesion molecule 1 (sVCAM-1). Plasma ET-1 was significantly elevated in SLE compared to Non-SLE (p=0.0042). Stratification by HTN status showed ET-1 elevation in female SLE Non-HTN (p=0.0137) and SLE HTN (p=0.0018) versus sex-matched controls, with no differences in males. Similarly, sVCAM-1 was elevated in female SLE Non-HTN (p=0.0073) and SLE HTN (p< 0.0001). Additionally, plasma ET-1 positively associated with sVCAM-1 in females (r=0.3147; p=0.0016). In female B6.Nba2 mice treated with topical TLR7/8 agonist R848 (100 µg/30 µl; twice weekly for 4 weeks), significant cardiovascular dysfunction was observed at 16 weeks, including reduced ejection fraction, renal glomerular fibrosis, and cardiac perivascular fibrosis. Left ventricle (LV) ET-1 was increased in R848 versus acetone controls (p=0.0195), with no kidney changes. VCAM-1 was upregulated in R848 LV (p=0.0273), coinciding with reduced endothelin receptor B (ETBR) expression (p=0.0007). Daily oral sitaxsentan (ETAR antagonist; 10mg/kg) preserved LV systolic function at 16 weeks (p=0.0363). However, sitaxsentan increased conscious glomerular filtration rates compared to R848 alone (p=0.0021). In vitro, in a reductionist model of SLE associated HTN, female HRECs exposed to HTN-like biaxial stretch and stimulated with SLE plasma showed significant upregulation of ETAR (p=0.0159) and VCAM-1 (p=0.0009), with no ETBR changes, compared to Non-SLE plasma. In summary, ET-1 is elevated in females with SLE and associates with endothelial activation. The female B6.Nba2 model demonstrates ET system dysregulation in SLE-associated CVD which is partially alleviated by ETAR antagonism. In vitro, SLE plasma upregulates ETAR and endothelial activation in HRECs under HTN-like stretch. These findings support further exploration of endothelial ETAR’s pathological role in SLE-associated CVD and highlight potential benefits of endothelin antagonists in SLE patients with cardiovascular dysfunction. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

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