Background and Purpose: Kawasaki disease (KD) is an acute, self-limiting vasculitis with an elusive etiology and can cause vascular endothelial injury. Exosomes derived from induced pluripotent stem cells (iPS-EXO) can exhibit anti-inflammatory, anti-oxidation, and anti-apoptosis properties. The objective of study is to explore the therapeutic effects of iPS-EXO on KD, and try to illuminate the underlying mechanisms. Experimental Approach: Mouse KD model with coronary arteritis induced by Candida albicans wall water-soluble fraction (CAWS) and human umbilical vein endothelial cell (HUVEC) injury KD model induced by tumor necrosis factor-alpha (TNF-α) were established to assess the anti-inflammatory and anti-apoptotic effects of iPS-EXO on KD. Key Results: In vivo experiments revealed that iPS-EXO could significantly inhibit the CD45-positive leukocyte infiltration, mitigate tissue fibrosis, down-regulate the expressions of inflammatory cytokines and chemokines, and reduce vascular endothelial cell apoptosis around coronary arteries of KD mice. In vitro results showed that iPS-EXO could also effectively inhibit TNF-α induced HUVEC inflammation and apoptosis by down-regulating inflammatory cytokines and chemokines, reducing TUNEL positive and flow cytometry apoptotic cells, and decreasing BAX/BCL-2 levels. However, these effects could be reversed by the AMPK inhibitor compound C (CC) and hsa-miR-1976-KO iPS-EXO. Conclusions and Implications: The further mechanism study based on bioinformatics analysis and western blotting indicated that iPS-EXO may exert anti-inflammatory and anti-apoptosis effects on KD through endogenous hsa-miR-1976 binding to CD40 to activate the AMPK/mTOR/NF-κB pathway, suggesting that iPS-EXO may be a promising therapeutic candidate for KD. KEYWORDS: Kawasaki disease (KD), Exosomes derived from induced pluripotent stem cells (iPS-EXO), Endothelial cells, Apoptosis, Inflammation

Kawasaki Disease (KD) is an acute and self-limiting vasculitis of unknown etiology that mainly occurs in infancy and can lead to vascular endothelial injury. Hesperidin (HES) is an economical dietary biological flavonoid with anti-oxidant, anti-inflammatory, and anti-apoptotic pharmacological effects. The main objective of this study was to investigate the protective effects of HES on KD, and try to elucidate the underlying mechanism. The Candida albicans water-soluble fraction (CAWS) was used to induce coronary arteritis of KD mouse model in vivo, and tumor necrosis factor α (TNF-α) was employed to induce human umbilical vein endothelial cell (HUVEC) injury of KD cell model in vitro to investigate the anti-inflammatory and anti-apoptotic effects of HES on KD. Our in vivo results showed that HES significantly reduced coronary artery injury in KD mice by alleviating pericoronary inflammatory infiltration and tissue fibrosis, inhibiting inflammatory cytokines and chemokines expressions, and decreasing vascular endothelial cell apoptosis. Our in vitro study confirmed that HES had the opposite ability of the NF-κB agonist NF-ĸB activator 1 (ACT1) to significantly alleviate the inflammatory response, CellROX level, and apoptosis by decreasing BAX/BCL-2 and Cleaved Caspase-3 levels as well as reducing TUNEL positive cells and the ratio of flow cytometry apoptotic cells in TNF-α induced HUVECs. The further mechanism study based on bioinformatics analysis and western blot demonstrated that HES could protect against vascular inflammation and cell apoptosis of KD through inhibiting the TLR4/IĸBα/NF-ĸB pathway, suggesting that HES may be a promising therapeutic candidate for KD.