Abstract Body: Kawasaki disease (KD) is an acute vasculitis that primarily affects medium-sized arteries, especially the coronary arteries, in children. It is the leading cause of acquired heart disease in children in developed countries. Immune dysregulation and systemic inflammation underlie its pathogenesis. Our group previously demonstrated that a mouse model of KD induced by Candida albicans water-soluble fraction (CAWS) exhibits vascular dysfunction mediated by Toll-like receptor 4 (TLR4) activation.
Artesunate (ART), an anti-malarial agent, was recently identified as an inhibitor of the MD2/TLR4 signaling pathway. Here, we tested the hypothesis that ART attenuates vascular dysfunction and vasculitis in the CAWS-induced KD mouse model. Male C57BL/6J mice (5–6 weeks old) were treated with CAWS (4 mg/day, intraperitoneally for 5 days) or vehicle (control). Based on our previous findings showing established vascular inflammation by day 7 post-induction, ART treatment (25 mg/kg/day, i.p.) was initiated on day 7 and continued for 3 weeks (KD+ART group). On day 28, hearts and abdominal aorta (AA) were collected for histological and vascular function analysis.
CAWS induced vasculitis in all mice (5/5). ART treatment reduced vasculitis severity in the coronary arteries by 60% and in the AA by 20%. Functionally, KD mice exhibited hypercontractility to U46619 in the AA, which was reversed by ART treatment [Emax (% of 120 mM KCl response): Ctrl: 254 ± 37; KD: 396 ± 10*; KD+ART: 258 ± 35; P < 0.05 vs. Ctrl and KD+ART]. KD also induced endothelial dysfunction, shown by reduced acetylcholine (ACh)-mediated vasodilation, which was restored by ART [pD2: Ctrl: 9.1 ± 0.1; KD: 8.1 ± 0.1*; KD+ART: 8.9 ± 0.2; P < 0.05 vs. Ctrl and KD+ART]. No changes were observed in KCl-induced contractility or sodium nitroprusside-induced vasodilation. Data for vascular function are presented as mean ± standard error of the mean.
In conclusion, ART effectively mitigates vascular dysfunction and reduces vasculitis in a KD mouse model. These findings highlight ART’s potential as a therapeutic strategy for reducing cardiovascular complications in patients with KD. Ongoing studies aim to delineate the immune cell landscape and molecular mechanisms through which ART confers vascular protection in KD.