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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1928.)
© 2001 American Heart Association, Inc.

Vascular Biology

Mast Cell Chymase Inhibits Smooth Muscle Cell Growth and Collagen Expression In Vitro

Transforming Growth Factor-ß1-Dependent and -Independent Effects

Yenfeng Wang; Naotaka Shiota; Markus J. Leskinen; Ken A. Lindstedt; Petri T. Kovanen

From the Wihuri Research Institute, Helsinki, Finland.

Reprint requests to Petri T. Kovanen, MD, PhD, Wihuri Research Institute, Kalliolinnantie 4, FIN-00140 Helsinki, Finland. E-mail petri.kovanen{at}wri.fi

In the vulnerable areas of fibrous caps of advanced atherosclerotic lesions, chymase-containing mast cells are present. In such areas, the numbers of smooth muscle cells (SMCs) and the content of collagen are reduced. In this in vitro study, we found that the addition of chymase, isolated and purified from rat serosal mast cells, to cultured rat aortic SMCs of the synthetic phenotype (s-SMCs) inhibited their proliferation by blocking the G₀/G₁S transition in the cell cycle. Rat chymase and recombinant human chymase inhibited the expression of collagen type I and type III mRNA in s-SMCs and in human coronary arterial SMCs. The growth-inhibitory effect of chymase was partially reversed by addition to the culture medium of an antibody capable of neutralizing the activity of transforming growth factor-ß1 (TGF-ß1). Immunocytochemistry showed that the s-SMCs expressed and synthesized extracellular matrix-associated TGF-ß1. On exposure to mast cell chymase, the extracellular matrix-associated latent TGF-ß1 was released and activated, as demonstrated by immunoblotting and by an ELISA with TGF-ß1 type II receptor for capture. When added to s-SMCs, such chymase-released TGF-ß1 was capable of inhibiting their growth. In contrast, the inhibitory effect of chymase on collagen synthesis by s-SMCs did not depend on TGF-ß1. Taken together, the findings support the hypothesis that chymase released from activated mast cells in atherosclerotic plaques contributes to cap remodeling.

Key Words: atherosclerosis • smooth muscle cells • transforming growth factor-ß • collagen • chymase

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