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 breakdown of the vascular extracellular matrix (e.g., normal tissue repair, remodeling, 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 isolated rat aortic tissue (detectable after 1 min of thrombin exposure). This secretion was mediated by an unidentified thrombin receptor, distinct from the proteinase activated receptors (PAR)-1 and -2. Protein tyrosine kinase/phosphatase activity differentially modulated the basal and the thrombin-induced release of MMP-2. The inhibitors of protein tyrosine kinase, herbymicin A, genistein, and tyrphostin 1288 (1 to 100 microM), 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 microM), selectively inhibited the thrombin-induced, but not the basal, release of MMP-2. Rapid release of vascular MMP-2 by thrombin could contribute to short-term processes where thrombin is involved such as the regulation of platelet aggregation and vascular reactivity. Vascular tyrosine kinase/phosphatase likely modulates this action of thrombin to prevent exaggerated platelet aggregation, thrombosis, and vasospasm.
Fernandez-Patron
C
C
Perinatal Research Centre, Department of Obstetrics/Gynaecology, University of Alberta, Edmonton, Canada.
Zhang
Y
Y
Radomski
M W
MW
Hollenberg
M D
MD
Davidge
S T
ST
D000818:Animals; D001011:Aorta / Q000378:metabolism*; D006490:Hemostatics / Q000494:pharmacology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013917:Thrombin / Q000494:pharmacology*
D006490:Hemostatics; D011505:Protein-Tyrosine Kinases; D017027:Protein Tyrosine Phosphatases; D013917:Thrombin; D020778:Matrix Metalloproteinase 2