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Modulation of thrombin and thrombin receptor peptide mitogenicity by human lung mast cell tryptase
T Hartmann1, S J Ruoss, G H Caughey
1Cardiovascular Research Institute, University of California, San Francisco 94143-0911.
Abstract:
In previous studies, mast cell tryptase acted as a potent mitogen for fibroblasts from human lung and rodent embryonic tissue but failed to stimulate growth of cultured rat aortic vascular smooth muscle cells (VSMC). The current study shows that tryptase inhibits DNA synthesis in VSMC stimulated by thrombin. However, it does not affect the stimulation of DNA synthesis by the synthetic thrombin receptor peptide Ser-Phe-Phe-Leu-Arg-Asn-Pro (SFFLRNP), which mimics the amino-terminus of thrombin receptor proteolytically activated by thrombin. Nor does tryptase alter the mitogenic response of VSMC to purified growth factors, such as platelet-derived growth factor (PDGF). These data suggest that tryptase inhibits thrombin-induced DNA synthesis without interfering with intracellular mitogenic signaling pathways activated by thrombin or other growth factors. This study further suggests that tryptase neither cleaves nor inactivates thrombin. Therefore, inhibition of thrombin's mitogenic effects by tryptase is not mediated by destruction of thrombin itself. The inhibition by tryptase of thrombin-induced DNA synthesis in VSMC contrasts with the stimulatory effect of tryptase on fibroblasts, in which synergy is observed with thrombin, with thrombin receptor peptide and with other growth factors. These data provide in vitro evidence that mast cell tryptase interferes with thrombin-stimulated vascular smooth muscle growth and suggest that tryptase is a multifunctional growth factor whose actions are cell specific.
Insights
Mast cell tryptase inhibits vascular smooth muscle cell growth stimulated by thrombin, but not by other growth factors. This suggests tryptase has cell-specific effects on vascular smooth muscle cells.
Area of Science:
- Vascular Biology
- Cell Signaling
- Mast Cell Biology
Background:
- Mast cell tryptase is a known mitogen for fibroblasts.
- Previous studies showed tryptase does not stimulate vascular smooth muscle cell (VSMC) growth.
Purpose of the Study:
- To investigate the effect of mast cell tryptase on thrombin-stimulated DNA synthesis in VSMC.
- To determine the mechanism by which tryptase influences VSMC growth.
Main Methods:
- Cultured rat aortic VSMC were stimulated with thrombin, thrombin receptor peptide (SFFLRNP), or growth factors (PDGF).
- DNA synthesis was measured in the presence or absence of mast cell tryptase.
- Tryptase activity on thrombin was assessed.
Main Results:
- Tryptase inhibited thrombin-induced DNA synthesis in VSMC.
- Tryptase did not affect VSMC DNA synthesis stimulated by SFFLRNP or PDGF.
- Tryptase did not cleave or inactivate thrombin.
- Tryptase's effect on VSMC contrasts with its stimulatory effect on fibroblasts.
Conclusions:
- Mast cell tryptase inhibits thrombin-stimulated VSMC growth via a mechanism independent of direct thrombin inactivation.
- Tryptase exhibits cell-specific functions, acting as a mitogen for fibroblasts but an inhibitor for VSMC.
- These findings highlight tryptase's complex role in regulating vascular smooth muscle cell proliferation.