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(Circulation Research. 1999;84:74-83.)
© 1999 American Heart Association, Inc.

Original Contribution

Heparin Proteoglycans Released From Rat Serosal Mast Cells Inhibit Proliferation of Rat Aortic Smooth Muscle Cells in Culture

Yenfeng Wang, Petri T. Kovanen

From the Wihuri Research Institute, Helsinki, Finland.

Abstract—Mast cells are present in the human arterial intima. To study whether mast-cell degranulation influences the rate of proliferation of smooth muscle cells, we cocultured sensitized (IgE-bearing) rat serosal mast cells and rat aortic smooth muscle cells (SMCs). When sensitized mast cells were stimulated to degranulate with antigen, the rate of proliferation of the cocultured SMCs decreased sharply. This inhibitory effect was found to be due mainly to the very high molecular weight (M_r) heparin proteoglycans (average M_r 750 000) released from the stimulated mast cells. When the heparin proteoglycans were purified from mast-cell granule remnants and added to the SMC culture, they were found to block the cell cycle at the G₀S transition and the exit from the G₂/M phase, their inhibitory effect resembling that of commercial heparin. However, in contrast to the reported dependence of the inhibitory effect of commercial heparin on the release of transforming growth factor-ß from serum, the inhibitory effect of the mast cell–derived heparin proteoglycans in the presence of serum was not transforming growth factor-ß dependent. Moreover, the effect of the mast cell–derived heparin proteoglycans was more efficient than that of commercial heparins of high (average M_r 15 000) and low (average M_r 5000) molecular weight. We also purified heparin glycosaminoglycans (average M_r 75 000) from the mast cell–derived heparin proteoglycans and found that they also inhibited SMC growth efficiently, although less strongly than their parent heparin proteoglycans. These results reveal, for the first time, that mast cells are able to regulate SMC growth. Thus, activated mast cells, by releasing heparin proteoglycans, possibly participate in the regulation of SMC growth in the human arterial intima, the site of atherogenesis.

Key Words: atherosclerosis • heparin proteoglycan • mast cell • proliferation • smooth muscle cell

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