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

Abstract

Abstract-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 G 0 /G 1 3 S 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-␤1 (TGF-␤1). Immunocytochemistry showed that the s-SMCs expressed and synthesized extracellular matrix-associated TGF-␤1. On exposure to mast cell chymase, the extracellular matrix-associated latent TGF-␤1 was released and activated, as demonstrated by immunoblotting and by an ELISA with TGF-␤1 type II receptor for capture. When added to s-SMCs, such chymase-released TGF-␤1 was capable of inhibiting their growth. In contrast, the inhibitory effect of chymase on collagen synthesis by s-SMCs did not depend on TGF-␤1. Taken together, the findings support the hypothesis that chymase released from activated mast cells in atherosclerotic plaques contributes to cap remodeling.

Mast Cell Chymase Modifies Cell-Matrix Interactions and Inhibits Mitogen-Induced Proliferation of Human Airway Smooth Muscle Cells

“…Our data and those reported by others (51) suggest that chymase inhibits the growth of human airway and vascular smooth muscle cells in vitro due to effects on matrix structure and to activation of TGF-␤. In contrast, in vivo data suggest that transgenic overexpression of a rat chymase in vascular smooth muscle promotes cell proliferation, possibly through production of angiotensin II (52).…”

“…In some systems CD44 has been shown to act as a docking site for proteolytically active MMP-9 (57); immobilized active MMP-9 then cleaves latent TGF-␤ to its active form (58). Interestingly, while mast cell-derived chymase has been shown to release latent TGF-␤ from epithelial cell cultures (59), it has a variable ability to activate latent TGF-␤ directly (51,59,60). One could speculate that local release of chymase by mast cells, and potentially by ASM cells (61), activates MMP-9 and induces the release of latent TGF-␤, which, in turn, is activated by either MMP-9 or chymase.…”

“…Paradoxically, chymase indirectly may serve to limit some of the pathological changes seen in chronic severe asthma. For example, chymase has been shown to inhibit the expression of collagen, inhibit vascular smooth muscle proliferation, and induce apoptosis (37,51). In addition, increased levels of active TGF-␤ may actually prevent smooth muscle cell hyperplasia by inhibiting the response to growth factors (62,63).…”

Expression Sites of Neural Stem Cell-Related Genes in the Monkey Retina

“…However, tryptase is involved in tissue fibrosis, and chymase induces apoptosis of cells with relatively low differentiation, including vascular smooth muscle cells, bronchial smooth muscle cells, and cardiomyocytes [16][17][18][19][20]. In other words, if we presume that there are undifferentiated cells in the fovea, then with regard to the action of these serine proteases, idiopathic epiretinal membranes may develop when tryptase activity is predominant, and idiopathic macular holes may develop when chymase activity is predominant.…”

Role of Chymase-Dependent Angiotensin II Formation in Regulating Blood Pressure in Spontaneously Hypertensive Rats

“…Shiota et al (21) reported that RMCP I mRNA expression in SHR hearts was significantly higher than in WKY rat hearts. RMCP I may be involved in cardiovascular remodeling via the degradation of fibronectin (22,23) and by the activation of transforming growth factor-β (24,25). On the other hand, RMCP II may contribute to an increase of vascular permeability (26).…”