© 1998 American Heart Association, Inc.
Original Contributions |
Metalloproteinase Blockade by Local Overexpression of TIMP-1 Increases Elastin Accumulation in Rat Carotid Artery Intima
From the Departments of Surgery (R.F., H.L., E.A., M.C., A.W.C.) and Pathology (D.H.), University of Washington School of Medicine, Seattle; and the Department of Biochemistry (B.S.), University of Texas Health Center at Tyler, Tex.
Correspondence to Dr Alexander W. Clowes, University of Washington, Department of Surgery, Box 356410, Seattle, WA 98195.
Abstract—We have recently demonstrated that the blockade of matrix metalloproteinases by local overexpression of the intrinsic inhibitor tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) reduces intimal hyperplasia. We now report a major change in the elastin content of the intima of rat carotid arteries seeded with TIMP-1–overexpressing smooth muscle cells. To understand the mechanism responsible for elastin accumulation, synthesis and degradation of elastin in TIMP-1 and control cell–seeded rats were measured. There were no differences in elastin mRNA or elastin synthesis, as documented by 14[C]proline incorporation between 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 was detected by elastin zymography and was decreased in TIMP-1 cell–seeded vessels. The 28 kD elastolytic activity was inhibited by exogenously added TIMP-1 and EDTA but not by PMSF, suggesting that it was a metalloelastase. Therefore, we have demonstrated that a shift of the proteolytic balance toward protease inhibition by TIMP-1 overexpression does not change elastin synthesis but rather changes posttranslational processing, resulting in increased elastin accumulation.
Key Words: TIMP-1 • elastin • intima • extracellular matrix • zymography
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