Stock Angus T, Parsons Sarah, D'Silva Damian B, Hansen Jacinta A, Sharma Varun J, James Fiona, Starkey Graham, D'Costa Rohit, Gordon Claire L, Wicks Ian P
Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
Department of Forensic Medicine, Monash University, and Victorian Institute of Forensic Medicine, Melbourne, Victoria, Australia.
Arthritis Rheumatol. 2023 Feb;75(2):305-317. doi: 10.1002/art.42340. Epub 2022 Dec 20.
Remodeling of the coronary arteries is a common feature in severe cases of Kawasaki disease (KD). This pathology is driven by the dysregulated proliferation of vascular fibroblasts, which can lead to coronary artery aneurysms, stenosis, and myocardial ischemia. We undertook this study to investigate whether inhibiting fibroblast proliferation might be an effective therapeutic strategy to prevent coronary artery remodeling in KD.
We used a murine model of KD (induced by the injection of the Candida albicans water-soluble complex [CAWS]) and analyzed patient samples to evaluate potential antifibrotic therapies for KD.
We identified the mechanistic target of rapamycin (mTOR) pathway as a potential therapeutic target in KD. The mTOR inhibitor rapamycin potently inhibited cardiac fibroblast proliferation in vitro, and vascular fibroblasts up-regulated mTOR kinase signaling in vivo in the CAWS mouse model of KD. We evaluated the in vivo efficacy of mTOR inhibition and found that the therapeutic administration of rapamycin reduced vascular fibrosis and intimal hyperplasia of the coronary arteries in CAWS-injected mice. Furthermore, the analysis of cardiac tissue from KD fatalities revealed that vascular fibroblasts localizing with inflamed coronary arteries up-regulate mTOR signaling, confirming that the mTOR pathway is active in human KD.
Our findings demonstrate that mTOR signaling contributes to coronary artery remodeling in KD, and that targeting this pathway offers a potential therapeutic strategy to prevent or restrict this pathology in high-risk KD patients.
冠状动脉重塑是川崎病（KD）重症病例的常见特征。这种病理状态是由血管成纤维细胞增殖失调驱动的，可导致冠状动脉瘤、狭窄和心肌缺血。我们开展这项研究以调查抑制成纤维细胞增殖是否可能是预防KD冠状动脉重塑的有效治疗策略。
我们使用KD小鼠模型（通过注射白色念珠菌水溶性复合物[CAWS]诱导）并分析患者样本，以评估KD的潜在抗纤维化治疗方法。
我们确定雷帕霉素靶蛋白（mTOR）通路是KD的一个潜在治疗靶点。mTOR抑制剂雷帕霉素在体外能有效抑制心脏成纤维细胞增殖，并且在KD的CAWS小鼠模型中，血管成纤维细胞在体内上调了mTOR激酶信号传导。我们评估了mTOR抑制的体内疗效，发现雷帕霉素的治疗性给药减少了注射CAWS的小鼠冠状动脉的血管纤维化和内膜增生。此外，对KD死亡病例心脏组织的分析显示，位于发炎冠状动脉处的血管成纤维细胞上调了mTOR信号，证实mTOR通路在人类KD中是活跃的。
我们的研究结果表明，mTOR信号传导促成了KD中的冠状动脉重塑，并且靶向该通路为预防或限制高危KD患者的这种病理状态提供了一种潜在的治疗策略。
