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(American Journal of Pathology. 2006;168:685-694.)
© 2006 American Society for Investigative Pathology

Localization of Cysteine Protease, Cathepsin S, to the Surface of Vascular Smooth Muscle Cells by Association with Integrin ß3

Xian Wu Cheng^*, Masafumi Kuzuya^*, Kae Nakamura^*, Qun Di^*, Zexuan Liu^*, Takeshi Sasaki^*, Shigeru Kanda^*, Hai Jin, Guo-Ping Shi, Toyoaki Murohara^¶, Mitsuhiro Yokota and Akihisa Iguchi^*

From the Departments of Geriatrics,^* Cardiovascular Genome Science, and Cardiology, ^¶ Nagoya University Graduate School of Medicine, Nagoya, Japan; the Cardiovascular Department, College of Medical, Yanbian University, Yanji, China; and Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts

Smooth muscle cell (SMC) migration from the tunica media to the intima, a key event in neointimal formation, requires proteolytic degradation of elastin-rich extracellular matrix barriers. Although cathepsin S (Cat S) is overexpressed in atherosclerotic and neointimal lesions, its exact role in SMC behavior remains primarily unresolved. We examined the involvement of Cat S on SMC migration through an extracellular matrix barrier and its localization in SMCs. A selective Cat S inhibitor and the endogenous inhibitor cystatin C significantly attenuated SMC invasion across elastin gel. Western blotting and cell surface biotinylation analysis demonstrated localization of the 28-kd active form of Cat S on the SMC surface, consistent with its role in the proteolysis of subcellular matrices. Treatment with interferon- or interleukin-ß1 significantly augmented the ability of SMC membranes to degrade elastin along with a significant increase in the level of active Cat S compared with controls. Immunofluorescence and confocal microscopy showed a punctuated pattern of Cat S clusters at the periphery of SMCs; further studies demonstrated partial co-localization of Cat S and integrin ß3 at the cell surfaces. These findings demonstrate that active Cat S co-localizes with integrin ß3 as a receptor on the SMC surface, playing an important role in the invasive behavior of SMCs.

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