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(American Journal of Pathology. 2001;159:321-327.)
© 2001 American Society for Investigative Pathology

Regular Articles

Matrix Metalloproteinase-2 Is Associated with Tenascin-C in Calcific Aortic Stenosis

Bo Jian*, Peter L. Jones*, Quanyi Li*, Emile R. Mohler, III{dagger}, Frederick J. Schoen{ddagger} and Robert J. Levy*

From the Cardiology Research Laboratory,*
Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; the Department of Medicine,{dagger}
University of Pennsylvania Health System, Philadelphia, Pennsylvania; and the Department of Pathology,{ddagger}
Brigham and Women’s Hospital, Boston, Massachusetts

We previously showed that the expression of tenascin (TN-C), an extracellular matrix glycoprotein found in developing bone and atherosclerotic plaque, and matrix metalloproteinase-2 (MMP-2) are coordinated and interdependent in cultured vascular smooth muscle cells. In this study, we hypothesized that TN-C and MMP-2 are mechanistically involved in the pathobiology of calcific aortic stenosis. Human calcific aortic stenosis cusps demonstrated immunohistochemically prominent deposition of TN-C, MMP-2, and alkaline phosphatase activity, as well as MMP-2 gelatinolytic activity. Although far lesser amounts of TN-C were noted in several of the grossly non-calcified valve cusps, MMP-2 and AP were never detected. Further, when aortic valve interstitial cells (both sheep and human) were cultivated on collagen supplemented with TN-C, both MMP-2 mRNA expression and MMP-2 gelatinolytic activity (both pro and active forms), were up-regulated compared to control. These observations support the view that accumulation of first TN-C and then MMP-2 are associated with progression of calcification. The residual presence of these proteins in severe calcifications is indicative of their involvement in the pathogenesis.




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