Matrix metalloproteinase-9 in vascular lesions and endothelial regulation in Kawasaki disease

Abstract

Background: Matrix metalloproteinases (MMPs) contribute to extracellular remodeling in Kawasaki disease (KD). MMP-9 is an essential vasculature-remodeling factor but its role in the vascular lesions of KD is not understood. This study focused on MMP-9 regulation via cytokines in endothelial cells (ECs).&Methods and Results: Plasma and peripheral blood mononuclear cells were obtained from 30 KD patients, and 15 non-febrile and 25 febrile children. Plasma MMP-1, -2, -9, and tissue inhibitor of MMP (TIMP)-1 and -2 were measured by 2-step sandwich ELISA. Immunohistology was performed on coronary arterial lesions (CAL) from a patient who died of KD in the acute phase. MMP-9 mRNA expression in human umbilical ECs (HUVECs) treated with plasma or cytokines, and in mononuclear cells was measured by semi-quantitative reverse transcrip-tion-polymerase chain reaction. Plasma MMP-1, -2 and TIMP-2 levels were normal for KD. Plasma MMP-9 and TIMP-1 levels increased during the acute phase of the disease (P<0.001 vs each control). MMP-9 stained diffusely in CAL. MMP-9 mRNA levels were higher in HUVECs treated with plasma in the acute and convalescent phases. Interleukin (IL)-1/S, IL-6, and tumor necrosis factor (TNF)-o- stimulated MMP-9 expression, whereas interferon (IFN)-y suppressed it. There was no MMP-9 mRNA elevation in mononuclear cells.&Conclusions: ECs are a source of MMP-9 in the vascular lesions of KD. MMP-9 is regulated by cytokines IL-1/S, IL-6, TNF-o-and IFN-y.