Background/Purpose: Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by autoantibody formation and immune complex deposition in target organs. While it is known that plasma endothelin-1 (ET-1) is elevated in patients with lupus and is associated with high rates of hypertension, renal injury, and cardiovascular disease, the underlying mechanisms contributing to cardiac complications associated with lupus are still unknown. Herein, we hypothesized that disease acceleration with the toll-like receptor 7/8 agonist, Resiquimod, would promote higher incidence of cardiac pathology and dysregulation of the ET system in a preclinical lupus murine model.

Methods: Female B6.Nba2 lupus prone mice aged 10-14 weeks were treated topically with either 30 uL of acetone or Resiquimod (R848;100µg/30µl) twice weekly for 4 weeks. Echocardiograms were performed every 4 weeks for 16 weeks to evaluate ejection fraction (EF), left ventricular wall thickening, and end-systolic and diastolic volumes. At 16 weeks, hearts and spleens were harvested, weighed and frozen or fixed for histological analysis. ET-1, endothelin receptor A (ET_A), and endothelin receptor B (ET_B) were analyzed by real-time PCR (RT-PCR), immunoblotting, and immunohistochemical analysis.

Results: Cardiac imaging showed R848-treated mice had increased left ventricular wall thickness at 4 weeks compared to acetone treatment (p< 0.01). After 16 weeks, mice previously treated with R848 for 4 weeks had profound cardiac dysfunction indicated by decreased EF (p< 0.001) and increased end-systolic volume (p< 0.01) compared to acetone treatment. R848-treated mice also exhibited profound cardio- (118.6 ± 1.014 vs. 187.7 ± 2.967; p< 0.0001) and splenomegaly (162.4 ± 33.3 vs. 658.3 ± 205.7; p< 0.05) at 16 weeks. Interestingly, histological analysis of the left ventricle demonstrated significantly increased perivascular fibrosis in the R848-treated mice compared to acetone (1.174 ± 0.1% vs. 1.651 ± 0.1%; p< 0.05). Interrogation of the cardiac ET system showed that R848-treated mice had significantly elevated ET-1 levels (p< 0.05), without a significant change in ET_A or ET_B receptor expression.

Conclusion: These data demonstrate that acceleration of lupus with the TLR7 agonist R848 increases cardiac dysfunction and pathological production of cardiac ET-1. Moreover, our model presents a novel avenue to better understand the role and contributions that the ET system plays in the development of lupus associated cardiac dysfunction.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-role-of-the-endothelin-system-in-the-development-of-tlr7-accelerated-lupus-associated-cardiac-dysfunction/