Yasutaka Nakashima1, Yasunari Sakai1, Yumi Mizuno2, Kenji Furuno2, Keiichi Hirono3, Shinichi Takatsuki4, Hiroyuki Suzuki5, Yoshihiro Onouchi6, Tohru Kobayashi7, Kazuhiro Tanabe8, Kenji Hamase9, Tomofumi Miyamoto10, Ryohei Aoyagi11,12, Makoto Arita11,12, Kenichiro Yamamura1, Tamami Tanaka1, Hisanori Nishio1, Hidetoshi Takada13, Shouichi Ohga1, Toshiro Hara2. 1. Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. 2. Kawasaki Disease Center, Fukuoka Children's Hospital, 5-1-1 Kashiiteriha, Higashi-ku, Fukuoka 813-0017, Japan. 3. Department of Pediatrics, Graduate School of Medicine, University of Toyama, Toyama 930-194, Japan. 4. Department of Pediatrics, Toho University Omori Medical Center, Tokyo 143-8540, Japan. 5. Department of Pediatrics, Wakayama Medical University, Wakayama 641-8509, Japan. 6. Department of Public Health, Chiba University Graduate School of Medicine, Chiba 260-0856, Japan. 7. Department of Management and Strategy, Clinical Research Center, National Center for Child Health and Development, Tokyo 157-0074, Japan. 8. Medical Solution Promotion Department, LSI Medience Corporation, Tokyo 101-8517, Japan. 9. Department of Drug Discovery and Evolution, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan. 10. Department of Pharmaceutical Health Care and Sciences, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan. 11. Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences (IMS), Tsurumi, Yokohama, Kanagawa 230-0045, Japan. 12. Division of Physiological Chemistry and Metabolism, Graduate School of Pharmaceutical Sciences, Keio University, Minato-ku, Tokyo 105-0011, Japan. 13. Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan.
Abstract
AIMS: Coronary arteritis is a life-threatening complication that may arise in the acute stage of Kawasaki disease (KD), the leading cause of systemic vasculitis in childhood. Various microorganisms and molecular pathogens have been reported to cause KD. However, little is known about the key molecules that contribute to the development of coronary arteritis in KD. METHODS AND RESULTS: To identify causative molecules for coronary arteritis in KD, we prospectively recruited 105 patients with KD and 65 disease controls in four different parts of Japan from 2015 to 2018. During this period, we conducted lipidomics analyses of their sera using liquid chromatography-mass spectrometry (LC-MS). The comprehensive LC-MS system detected a total of 27 776 molecules harbouring the unique retention time and m/z values. In the first cohort of 57 KD patients, we found that a fraction of these molecules showed enrichment patterns that varied with the sampling region and season. Among them, 28 molecules were recurrently identified in KD patients but not in controls. The second and third cohorts of 48 more patients with KD revealed that these molecules were correlated with inflammatory markers (leucocyte counts and C-reactive proteins) in the acute stage. Notably, two of these molecules (m/z values: 822.55 and 834.59) were significantly associated with the development of coronary arteritis in the acute stage of KD. Their fragmentation patterns in the tandem MS/MS analysis were consistent with those of oxidized phosphatidylcholines (PCs). Further LC-MS/MS analysis supported the concept that reactive oxygen species caused the non-selective oxidization of PCs in KD patients. In addition, the concentrations of LOX-1 ligand containing apolipoprotein B in the plasma of KD patients were significantly higher than in controls. CONCLUSION: These data suggest that inflammatory signals activated by oxidized phospholipids are involved in the pathogenesis of coronary arteritis in KD. Because the present study recruited only Japanese patients, further examinations are required to determine whether oxidized PCs might be useful biomarkers for the development of coronary arteritis in broad populations of KD. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Coronary arteritis is a life-threatening complication that may arise in the acute stage of Kawasaki disease (KD), the leading cause of systemic vasculitis in childhood. Various microorganisms and molecular pathogens have been reported to cause KD. However, little is known about the key molecules that contribute to the development of coronary arteritis in KD. METHODS AND RESULTS: To identify causative molecules for coronary arteritis in KD, we prospectively recruited 105 patients with KD and 65 disease controls in four different parts of Japan from 2015 to 2018. During this period, we conducted lipidomics analyses of their sera using liquid chromatography-mass spectrometry (LC-MS). The comprehensive LC-MS system detected a total of 27 776 molecules harbouring the unique retention time and m/z values. In the first cohort of 57 KDpatients, we found that a fraction of these molecules showed enrichment patterns that varied with the sampling region and season. Among them, 28 molecules were recurrently identified in KDpatients but not in controls. The second and third cohorts of 48 more patients with KD revealed that these molecules were correlated with inflammatory markers (leucocyte counts and C-reactive proteins) in the acute stage. Notably, two of these molecules (m/z values: 822.55 and 834.59) were significantly associated with the development of coronary arteritis in the acute stage of KD. Their fragmentation patterns in the tandem MS/MS analysis were consistent with those of oxidized phosphatidylcholines (PCs). Further LC-MS/MS analysis supported the concept that reactive oxygen species caused the non-selective oxidization of PCs in KDpatients. In addition, the concentrations of LOX-1 ligand containing apolipoprotein B in the plasma of KDpatients were significantly higher than in controls. CONCLUSION: These data suggest that inflammatory signals activated by oxidized phospholipids are involved in the pathogenesis of coronary arteritis in KD. Because the present study recruited only Japanese patients, further examinations are required to determine whether oxidized PCs might be useful biomarkers for the development of coronary arteritis in broad populations of KD. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Olga Vvedenskaya; Michal Holčapek; Michael Vogeser; Kim Ekroos; Peter J Meikle; Anne K Bendt Journal: J Mass Spectrom Adv Clin Lab Date: 2022-02-07