PROTEINASES AND RESTENOSIS IN THE HUMAN CORONARY-ARTERY - EXTRACELLULAR-MATRIX PRODUCTION EXCEEDS THE EXPRESSION OF PROTEOLYTIC ACTIVITY

To understand the balance of proteinase antiproteinase activity and th e production of extracellular matrix (ECM) at the site of arterial inj ury, we analyzed the composition of ECM and proteinase activity in nor mal internal mammary arteries, tissue samples obtained from atheroscle rotic coronary lesions and restenotic lesions obtained during directio nal coronary atherectomy. Histologically and biochemically, collagen a nd proteoglycans increased, and elastin decreased in samples from rest enotic lesions when compared to samples taken from patients undergoing their first revascularization (de novo). In contrast, cellularity was increased in samples obtained from de novo patients as compared tb sa mples obtained from restenotic lesions. Intrinsic activity of matrix m etalloproteinases (MMPs) was measured by using zymography and scanning all the lytic bands in zymographic gel. In these gels, identical amou nts of total protein were loaded in each lane. MMP activity was determ ined as % of the total (latent and active) MMPs after trypsin activati on (100%) in the normal artery. Intrinsic MMP activity was reduced to 6% +/- 1% in atherosclerotic lesions and 1% +/- 1% in restenotic lesio ns, when compared to activity found in normal (10% +/- 3%) arteries. B ased on Solubilization of fluorescein-conjugated elastin by the extrac ts, the MMP-mediated elastinolytic activity was 0.2 +/- 0.1, 8.8 +/- 1 .5, and 24.0 +/- 3 nmol/min/mg in restenotic, native atherosclerotic a nd normal tissue, respectively. The results suggested that, in arteria l tissue from patients with angiographic restenosis, there is an incre ased production of ECM collagen and a decrease in MMP activity compare d to both normal artery and atherosclerotic samples from de novo patie nts undergoing an initial revascularization procedure of a significant coronary artery lesion.