THROMBIN STIMULATES SMOOTH-MUSCLE CELL PROCOLLAGEN SYNTHESIS AND MESSENGER-RNA LEVELS VIA A PAR-1 MEDIATED MECHANISM

Thrombin is a serine protease involved in haemostasis which exerts a n umber of cellular effects, including stimulating mesenchymal cell migr ation, proliferation, and has been implicated both in normal wound hea ling and pathological conditions associated with hyperproliferation of smooth muscle cells such as atherosclerosis and restenosis. We hypoth esize that thrombin, in addition to its proliferative effects, may als o influence the deposition of matrix proteins at sites of vascular inj ury by directly stimulating smooth muscle cell procollagen production. 10 nM thrombin significantly stimulated rat aortic smooth muscle cell procollagen production by 34 +/- 3% compared to media control cells o ver a 48 h incubation period, and increased steady state alpha(1)(I) p rocollagen mRNA levels by up to 104 +/- 22%. These effects are mediate d via interaction of thrombin with the PAR-1 receptor since TRAP (Thro mbin Receptor Activating Peptide) stimulated procollagen production by 23 +/- 0.5%. In addition, conditioned medium from thrombin-treated ce lls stimulated procollagen production by 30 +/- 3% suggesting that thr ombin is acting via the production and/or release of an autocrine medi ator. These data suggest a novel role for thrombin in vascular wound h ealing and the development of pathological conditions associated with increased connective tissue deposition.