Metalloproteinase blockade by local overexpression of TIMP-1 increases elastin accumulation in rat carotid artery intima

被引:28
作者
Forough, R
Lea, H
Starcher, B
Allaire, E
Clowes, M
Hasenstab, D
Clowes, AW
机构
[1] Univ Washington, Sch Med, Dept Surg, Seattle, WA 98195 USA
[2] Univ Washington, Sch Med, Dept Pathol, Seattle, WA 98195 USA
[3] Univ Texas, Ctr Hlth, Dept Biochem, Tyler, TX 75710 USA
关键词
TIMP-1; elastin; intima; extracellular matrix; zymography;
D O I
10.1161/01.ATV.18.5.803
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:803 / 807
页数:5
相关论文
共 22 条
[1]   MOUSE MACROPHAGE ELASTASE [J].
BANDA, MJ ;
WERB, Z .
BIOCHEMICAL JOURNAL, 1981, 193 (02) :589-605
[2]  
CHOMCZYNSKI P, 1987, ANAL BIOCHEM, V162, P156, DOI 10.1016/0003-2697(87)90021-2
[3]   GENOMIC SEQUENCING [J].
CHURCH, GM ;
GILBERT, W .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES, 1984, 81 (07) :1991-1995
[4]   LONG-TERM BIOLOGICAL RESPONSE OF INJURED RAT CAROTID-ARTERY SEEDED WITH SMOOTH-MUSCLE CELLS EXPRESSING RETROVIRALLY INTRODUCED HUMAN GENES [J].
CLOWES, MM ;
LYNCH, CM ;
MILLER, AD ;
MILLER, DG ;
OSBORNE, WRA ;
CLOWES, AW .
JOURNAL OF CLINICAL INVESTIGATION, 1994, 93 (02) :644-651
[5]  
Davidson J, 1987, CONNECTIVE TISSUE DI, P29
[6]   MATRIX VESICLES ARE ENRICHED IN METALLOPROTEINASES THAT DEGRADE PROTEOGLYCANS [J].
DEAN, DD ;
SCHWARTZ, Z ;
MUNIZ, OE ;
GOMEZ, R ;
SWAIN, LD ;
HOWELL, DS ;
BOYAN, BD .
CALCIFIED TISSUE INTERNATIONAL, 1992, 50 (04) :342-349
[7]  
FERNS GAA, 1991, AM J PATHOL, V138, P1045
[8]   Overexpression of tissue inhibitor of matrix metalloproteinase-1 inhibits vascular smooth muscle cell functions in vitro and in vivo [J].
Forough, R ;
Koyama, N ;
Hasenstab, D ;
Lea, H ;
Clowes, M ;
Nikkari, ST ;
Clowes, AW .
CIRCULATION RESEARCH, 1996, 79 (04) :812-820
[9]   CLONING AND CHARACTERIZATION OF A CDNA-ENCODING THE BABOON TISSUE INHIBITOR OF MATRIX METALLOPROTEINASE-1 (TIMP-1) [J].
FOROUGH, R ;
NIKKARI, ST ;
HASENSTAB, D ;
LEA, H ;
CLOWES, AW .
GENE, 1995, 163 (02) :267-271
[10]   ELECTROPHORETIC ANALYSIS OF PLASMINOGEN ACTIVATORS IN POLYACRYLAMIDE GELS CONTAINING SODIUM DODECYL-SULFATE AND COPOLYMERIZED SUBSTRATES [J].
HEUSSEN, C ;
DOWDLE, EB .
ANALYTICAL BIOCHEMISTRY, 1980, 102 (01) :196-202