Matrix Metalloproteinases-2 and-9 in Areas of Extracellular Matrix Destruction and Angiogenesis in Coronary Artery Aneurysms in Kawasaki Disease

Abstract

Coronary artery aneurysms (CAA) can complicate Kawasaki Disease (KD) and lead to rupture, coronary thrombosis or coronary stenosis. CAA are characterized histologically by destruction of extracellular matrix (ECM), most notably elastic tissue in the vascular media; inflammatory cell infiltrates; and neovascularization. Matrix metaloproteinases (MMP) are known to regulate degradation and remodeling of the ECM and angiogenesis. MMP-2 and-9 have been implicated in the pathogenesis of abdominal aortic aneurysms and atherosclerosis, and elevated plasma levels of MMP-9 have been demonstrated in acute KD. We hypothesized that MMP are important in the pathogenesis of CAA development and vascular remodeling in KD. To determine if MMP are present in KD CAA, we performed immunohistochemistry for MMP-2 and -9 on paraffin-embedded formalin-fixed coronary artery tissue from 11 fatal acute KD cases and from 7 children who died of other causes. Although there was no significant quantitative difference in MMP-2 in KD and non-KD coronary arteries, there was a qualitative difference in the pattern of MMP-2 expression. In control and non-aneurysmal KD arteries, MMP-2 was present only in vascular smooth muscle cells and endothelial cells, whereas in KD CAA, MMP-2 was prominent in the thickened neointima, in smooth muscle cells migrating from the media into the neointima, and in endothelial cells in areas of adventitial angiogenesis. In contrast, there was a significant difference in the expression of MMP-9 in KD CAA and control coronary arteries (p≤0.01). MMP-9 was prominently expressed by mononuclear inflammatory cells in CAA but was not expressed in non-aneurysmal KD coronary arteries or in control subject coronary arteries. We conclude that MMP-2 and -9 are differentially expressed in CAA of KD patients when compared to non-aneurysmal KD or control coronary arteries. Differential expression of MMP may contribute to ECM degradation, neointimal proliferation, and local angiogenesis in KD CAA.