Effect of selective ganglion stimulation on hypertension in systemic lupus erythematosus

Effect of selective ganglion stimulation on hypertension in systemic lupus erythematosus

Keanna K. Johnson1, Viet Dinh2, Cassandra M. Young-Stubbs2, Caroline G. Shimoura2, Sarika Chaudhari2, Keisa W. Mathis2

1School of Public Health,2Department of Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, Texas

Purpose: Systemic lupus erythematous (SLE) is a female-dominant autoimmune disease that causes widespread inflammation in various organs. Inflammation precedes the prevalent hypertension in the disease. The cholinergic anti-inflammatory pathway (CAP) is an endogenous neuroimmune pathway that reduces inflammation upon stimulation. We hypothesize that stimulation of the CAP by selective activation of the superior cervical ganglion will halt disease progression and hypertension in SLE.

Methods: Female SLE (NZBWF1) and control (NZW) mice received unilateral microinjections of pAAV-hSyn-hM3D(Gq)-mCherry, a designer receptor exclusively activated by designer drug (DREADD), or pAAV-hSyn-mCherry (vehicle) at the superior cervical ganglion (SCG) at 32 weeks of age. SCG DREADD injections generate muscarinic receptors on SCG neurons that are activated by the designer drug, clozapine N-oxide (CNO), ultimately leading to neuronal stimulation and potentially activation of the CAP. At 33 weeks of age, mice with SCG DREADD received a daily s.c. injection of CNO (3mg/kg) for two weeks. At 35 weeks, mice received a catheter implant in the carotid artery to measure mean arterial pressure (MAP) for two consecutive days followed by euthanasia and tissue collection. Plasma was collected biweekly via retro-orbital bleeding. Plasma samples were used to quantify double-stranded (ds) DNA autoantibodies.

Results: dsDNA autoantibodies were higher in SLE than control mice (8.6e5 ± 1.8e5 vs. 5.1e4 ± 1.1e4 U/mL; p=0.0002; n=13). SCG DREADD did not change dsDNA autoantibody levels in SLE mice (1.1e6 ± 2.6e5 U/mL; p=0.1410; n=6) or control mice (5.4e4 ± 1.5e4 U/mL; p=0.6549; n=9). MAP was significantly higher in SLE mice compared to control mice (150 ± 9 vs. 122 ± 3 mmHg; p=0.0009; n=5–9). SCG DREADD did not change MAP in SLE mice (137 ± 2 mmHg; p=0.2572; n=6) or controls (127 ± 3 mmHg; p=0.7678; n=9).

Conclusion: These data suggest that selective activation of the CAP at the level of the SCG using DREADD did not significantly alter disease severity or blood pressure in female SLE mice with advanced disease. Future studies will determine the effect of selective ganglion stimulation on inflammatory outcomes.

Funding: Research reported in this abstract was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number R25HL125447. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.