Rapid release of matrix metalloproteinase (MMP)-2 by thrombin in the rat aorta: Modulation by protein tyrosine kinase/phosphatase

Matrix metalloproteinase-2 (MMP-2, gelatinase A) and thrombin contribute to many long-term (patho)physiological processes requiring the proteolytic br eakdown of the vascular extracellular matrix (e.g., normal tissue repair, r emodeling, tumor invasion, atherosclerosis plaque rupture). Thrombin (10 to 1000 nM, 0.5 to 50 U/ml) induced a rapid secretion of MMP-2 from freshly i solated rat aortic tissue (detectable after 1 min of thrombin exposure). Th is secretion was mediated by an unidentified thrombin receptor, distinct fr om the proteinase activated receptors (PAR)-1 and -2. Protein tyrosine kina se/phosphatase activity differentially modulated the basal and the thrombin -induced release of MMP-2. The inhibitors of protein tyrosine kinase, herby micin A, genistein, and tyrphostin 1288 (1 to 100 mu M), enhanced the basal release of MMP-2 but did not affect the thrombin-induced secretion of MMP- 2. The inhibitor of phosphotyrosine phosphatases, vanadate (100 mu M), sele ctively inhibited the thrombin-induced, but not the basal, release of MMP-2 . Rapid release of vascular MMP-2 by thrombin could contribute to short-ter m processes where thrombin is involved such as the regulation of platelet a ggregation and vascular reactivity. Vascular tyrosine kinase/phosphatase li kely modulates this action of thrombin to prevent exaggerated platelet aggr egation, thrombosis, and vasospasm.