Mechanism of HMGB1–RAGE in Kawasaki disease with coronary artery injury

Abstract

Background: Kawasaki disease (KD) is a common, yet unknown etiology disease in Asian countries, which causes acquired heart disease in childhood. It is characterized by an inflammatory acute febrile vasculitis of medium-sized arteries, particularly the coronary arteries. High-mobility group box-1 protein (HMGB1) is a non-histone chromosomalbinding protein present in the nucleus of eukaryotic cells, which contains 215 amino acid residues. Although the cellular signal transduction mechanisms of HMGB1 are currently unclear, the important role of the receptor for advanced glycation end-products (RAGE), the main receptor for HMGB1 has been reported in detail. The purpose of our study was to verify the mechanism and clinical significance of HMGB1-RAGE in coronary artery injury of Kawasaki disease. Methods: 52 blood samples of patients in KD were collected, and the coronary artery Z score was calculated according to the echocardiographic results. The Z score ≥ 2.0 was classified as coronary artery lesions (CAL); otherwise, it was no-coronary artery lesions (NCAL). In addition, the fever group and control group were set. Among them, the fever group were children with fever due to respiratory tract infection at the same time period as KD (heat peak ≥ 38.5 ℃). The normal group were children at a routine physical examination in the outpatient clinic of Nantong University and the physical examination center of the child care insurance, and there were no infectious diseases and heart diseases. The serum levels of HMGB1, RAGE, and NF-κB in each group were detected by ELISA. The animal model of KD was established using the New Zealand young rabbits. We used RT-qPCR/H&E staining/immunohistochemistry/ELISA and western blot to detect the level of HMGB1/RAGE and NF-κB. Results: In this study, we found that the HMGB1/RAGE/NF-κB axis was elevated in the serum of children with KD. In addition, an animal model of KD was subsequently prepared to examine the pathological changes of the coronary arteries. We found that the serum levels of HMGB1/RAGE/NF-κB in rabbits with KD were significantly higher than those of the control group. Moreover, the lumen diameter of the coronary artery was slightly enlarged, and the wall of the tube became thinner and deformed. In addition, the HMGB1/RAGE/NF-κB levels in the coronary artery were higher in the rabbits with KD in the acute phase. Conclusions: On the whole, the findings of this study demonstrate that the expression of HMGB1/RAGE/NF-κB is altered at different stages of KD, suggesting that the HMGB1/RAGE/NF-κB signaling pathway plays an important role in vascular injury in KD. The results of this study may have important implications for the early warning of coronary artery lesions in KD.

Tanshinone IIA Has a Potential Therapeutic Effect on Kawasaki Disease and Suppresses Megakaryocytes in Rabbits With Immune Vasculitis

“…The present study used rabbits with immune vasculitis as the animal model of human KD ( 20 , 23 , 24 ) to examine the effect of tanshinone IIA on inflammatory responses and especially, the megakaryocyte-platelet axis. In general, immune vasculitis could be established through intravenous injection of heterogeneous proteins; in this study, BSA was used to induce immune vasculitis in weanling rabbits.…”

Targeting RAGE to prevent SARS-CoV-2-mediated multiple organ failure: Hypotheses and perspectives

“…The involvement of RAGE/HMGB1 axis has been recently speculated in the development of the Kawasaki disease (KD), which is an acute and usually self-limiting vasculitis of the medium calibre vessels affecting almost exclusively children [ [137] , [138] , [139] ]. An aberrant response of the immune system to an infectious agent in genetically predisposed children seems to trigger the cascade that causes the illness, which has been recently associated with the common respiratory viruses, such as enteroviruses, adenoviruses, rhinoviruses, and coronaviruses [ 138 , 139 ].…”

“…Particularly, as suggested by data obtained in animal model of KD, HMGB1 might accumulate in coronary endothelial cells causing coronary vasculitis and promoting coronary artery dilatation via RAGE/NF-κB signalling. HMGB1 levels were found higher in children with KD than in healthy controls suggesting serum HMGB1 as an indicator of inflammation and coronary artery injury in this pathology [ 137 ].…”

AGE/Non-AGE Glycation: An Important Event in Rheumatoid Arthritis Pathophysiology

“…HMGB1 is a ligand of multiple receptors such as TLR-2, TLR-4, and TLR-9; IL-1 beta and RAGE initiate various inflammatory pathways, whereas sRAGE is a decoy of HMGB1 [91]. In the case of OA and Kawasaki disease (KD), mRNA expressions of HMGB1 and RAGE are both directly proportional to increased expression of NF-κB activation via RAGE signalling cascades [92,93]. HMGB1 binds to TLR-4 and activates NADPH oxidase in neutrophils, which activates p38, MAPK, and Akt pathways, leading to increased ROS generation [94].…”