METALLOPROTEINASE BLOCKADE BY LOCAL OVEREXPRESSION OF TIMP-1 INCREASES ELASTIN ACCUMULATION IN RAT CAROTID-ARTERY INTIMA

We have recently demonstrated that the blockade of matrix metalloprote inases by local overexpression of the intrinsic inhibitor tissue inhib itor of matrix metalloproteinase-1 (TIMP-1) reduces intimal hyperplasi a. We now report a major change in the elastin content of the intima o f rat carotid arteries seeded with TIMP-1-overexpressing smooth muscle cells. To understand the mechanism responsible for elastin accumulati on, synthesis and degradation of elastin in TIMP-1 and control cell-se eded rats were measured. There were no differences in elastin mRNA or elastin synthesis, as documented by (14)[C]proline incorporation betwe en TIMP-1 and control cell-seeded arteries. In contrast, there was an increase in cross-linked elastin in the TIMP-1 group. In addition, in TIMP-1 and control rats, an elastase activity of approximately 28 kD w as detected by elastin zymography and was decreased in TIMP-1 cell-see ded vessels. The 28 kD elastolytic activity was inhibited by exogenous ly added TIMP-1 and EDTA but not by PMSF, suggesting that it was a met alloelastase. Therefore, we have demonstrated that a shift of the prot eolytic balance toward protease inhibition by TIMP-1 overexpression do es not change elastin synthesis but rather changes posttranslational p rocessing, resulting in increased elastin accumulation.