Abstract 12651: C-jun N-terminal Kinase is a Novel Therapeutic Target for Controlling the Development of Kawasaki Disease-related Arterial Aneurysm
Introduction: Kawasaki disease (KD), which is the most common multisystem vasculitis with unknown origin in childhood, and causes inflammation of coronary arteries leading to aneurysms, the most severe complication. The treatment of KD patients by high-dose intravenous immunoglobulin (IVIG) greatly reduces the incidence of coronary aneurysm; however, the incidence of aneurysm is still 5% in treated patients. Inhibiting the progression of aneurysm is required to rescue such patients. c-Jun N-terminal kinase (JNK) is a stress-activated protein kinase. JNK activity is essential for the progression of abdominal aortic aneurysms. We have focused on common inflammatory changes in these aneurysms. This study aimed to determine whether a JNK inhibitor prevents aneurysms in KD in an animal model, by observing tenascin-c (TnC) expression, a matricellular protein, as a tissue remodeling marker.
Methods: A Candida albicans-induced KD-like vasculitis model was established in C57BL/6 mice. The JNK inhibitor SP6000125 (40 mg/pellet, 60-day release, 30 mg/kg/day) was administered under the skin of a posterior cervical lesion 1 day before creation of the mouse model (JNK group, n=10). We compared the incidence of arterial lesions between the JNK group and the placebo group (n=20) 8 weeks after insertion of the JNK inhibitor. We performed quantification measurements of the aneurysm and histological analyses, including hematoxylin-eosin (H-E) staining, Elastica van Gieson (EVG) staining, macrophage staining (Mac-3), and TnC expression.
Results: The incidence of macroscopic aneurysms in the JNK group was significantly lower compared with that in the placebo group (1/10, 10%, versus 13/20, 65%). Furthermore, the external diameter of the aneurysm in JNK group was significantly smaller than that in placebo group. In histological analysis, the aneurysm in the JNK group had lower TnC expression, macrophage infiltration, and fragmentation of elastic fibers compared with that in the placebo group.
Conclusions: A JNK inhibitor prevents the development of aneurysm in a Candida-induced KD mouse model. JNK inhibitors may be a therapeutic target for preventing arterial tissue remodeling and controlling aneurysm formation in KD patients.
- © 2013 by American Heart Association, Inc.