Abstract Body: Systemic lupus erythematosus (SLE), an autoimmune disorder more prevalent in women, adversely impacts the cardiovascular system. SLE is associated with elevated endothelin-1 (ET-1), an inflammatory vasoconstrictor, and increased endothelin receptor A (ET_AR) signaling. The cause of elevated ET-1 and renal endothelial ET_AR in SLE remains unclear. This study investigates how hypertension (HTN) and SLE influence ET-1 regulation in human subjects, human renal endothelial cells (HRECs), and the B6.Nba2 preclinical model of SLE-associated cardiovascular disease. In a pilot cohort (n=37 females; 20 Non-SLE, 17 SLE), plasma ET-1 was significantly elevated in SLE subjects (p=0.0108). Stratification by HTN revealed only SLE HTN subjects had elevated ET-1 compared to Non-SLE Non-HTN controls (p=0.0025). ET-1 positively correlated with systolic blood pressure (r=0.3850; p=0.0347). A validation cohort confirmed these findings: Non-SLE Non-HTN (n=46; F/M=31/15), Non-SLE HTN (n=36; F/M=29/7), SLE Non-HTN (n=49; F/M=34/15), SLE HTN (n=50; F/M=35/15). ET-1 was elevated only in SLE HTN vs. Non-SLE Non-HTN (p=0.0090). When stratified by sex, this was true for women (p=0.0007), but not men. Female SLE HTN subjects had higher ET-1 than male counterparts (p=0.0009). ET-1 correlated with systolic BP in females (r=0.2691; p=0.0035), but not males.
To assess how female plasma affects renal endothelial ET-1 regulation, HRECs were stimulated with Non-SLE or SLE female plasma under 10% biaxial stretch (n=6/group). SLE plasma reduced Edn1 (p=0.0022) and Ednra (p=0.0408) mRNA, with a trend toward increased Ednrb (p=0.0655). Protein analysis showed no change in ET_BR, but ET_AR was elevated in SLE (p=0.0159), along with VCAM-1 (p=0.0009).
In vivo, male and female B6.Nba2 mice were treated with Resiquimod (R848; 100 µg/30 µL) twice weekly. Female R848-treated mice had increased cardiac ET-1 vs. both sex and vehicle controls (p=0.0002, p=0.0009). Both sexes showed elevated plasma sVCAM-1 (p=0.0286, p=0.0028), with a trend toward correlation between cardiac ET-1 and sVCAM-1 in females (r=0.4693; p=0.0573). ET_AR antagonism with sitaxsentan (10 mg/kg) in R848-treated females (n=3 R848, n=4 R848+sitaxsentan) blunted the decline in cardiac ejection fraction (p=0.0363) and increased glomerular filtration rate (p=0.0095). These findings highlight sex-dependent ET-1 elevation in SLE, the role of HTN, and suggest ET_AR antagonism may protect against SLE-related cardiovascular injury.