Evidence for proteinase‐activated receptor‐2 (PAR‐2)‐mediated mitogenesis in coronary artery smooth muscle cells

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Abstract
This study investigates, whether in addition to the thrombin receptor (PAR‐1), the proteinase‐activated receptor‐2 (PAR‐2) is present in vascular smooth muscle cells (SMC) and mediates mitogenesis. PAR‐2 is activated by low concentrations of trypsin and the synthetic peptide SLIGRL. Stimulation of bovine coronary artery SMC by trypsin (2 nM) caused a 3 fold increase in DNLA‐synthesis. A similar effect was observed with 10 nM thrombin. Trypsin‐induced mitogenesis was inhibited by soybean trypsin inhibitor, indicating that the proteolytic activity of the enzyme was required for its mitogenic effect. The specific PAR‐2‐activating peptide SLIGRL or the PAR1‐activating peptide SFFLRN did not elicit mitogenesis. When the SMC were exposed to SLIGRL (40 nM), a homologous desensitization of cytosolic Ca2+ mobilization was found after subsequent stimulation with trypsin (40 nM) but not thrombin (15 nM). Trypsin (2 nM) as well as SLIGRL (100 μM) activated the nuclear factor κB (NFκB) with a maximum response 2 h after stimulation of the SMC. This suggests that both agonists acted via a common receptor, PAR‐2. Maximum activation of NFκB by thrombin (10 nM) was detected after 4–5 h. These data suggest that PAR‐2 is present in coronary SMC and mediates a mitogenic response. Activation of NFκB via either PAR‐1 or PAR‐2 does not predict mitogenesis. British Journal of Pharmacology (1999) 126, 1735–1740; doi:10.1038/sj.bjp.0702509

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