Apolipoprotein E knockout mice over-expressing human tissue inhibitor of metalloproteinase 1 are protected against aneurysm formation but not against atherosclerotic plaque development.
OBJECTIVE
We investigated the effect of plasma levels of human tissue inhibitor of metalloproteinase (hTIMP)-1 on arterial lesion development and aneurysm formation in apolipoprotein-E-deficient mice (ApoE(-/-)).


METHODS
Control and transgenic mice were fed either a chow diet or a high-fat diet for 90 and 180 days.


RESULTS
hTIMP-1 has a tendency to decrease atherosclerotic lesions, but did not attain significance (approximately 6% reduction in hTIMP-1(+/+), p = 0.075, and approximately 4% in hTIMP-1(+/0), p = 0.088 vs. control). Immunohistological and histological analyses revealed a reduction in macrophage accumulation (23% of control in hTIMP(+/0), p = 0.065, and 49% of control in hTIMP(+/+), p < 0.05) but not in collagen degradation within the lesion in transgenic mice. Moreover, elastin degradation in sites of pseudo-microaneurysms was reduced in transgenic mice (37% of control in hTIMP-1(+/0), p < 0.05, and 50% of control in hTIMP-1(+/+), p < 0.05). DNA array analysis of matrix metalloproteinase (MMP) expression followed by real-time PCR quantification revealed a significant up-regulation of MMP-3, MMP-12 and MMP-13 in arterial lesions of ApoE(-/-) mice fed a high-fat diet in comparison with the same mice fed a chow diet.


CONCLUSIONS
These data show that hTIMP-1 reduces aneurysm formation in ApoE(-/-) mice but does not protect them against the development of arterial lesions.
Cuaz-Pérolin
Clarisse
C
INSERM U-545, Institut Pasteur de Lille, Département d'Athérosclérose, Lille, France.
Jguirim
Imen
I
Larigauderie
Guilhem
G
Jlassi
Awatef
A
Furman
Christophe
C
Moreau
Martine
M
Chapman
M John
MJ
Fruchart
Jean-Charles
JC
Slimane
Mohamed Naceur
MN
Mezdour
Hafid
H
Rouis
Mustapha
M
D000783:Aneurysm / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D001158:Arteries / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000473:pathology / Q000503:physiopathology*; D003094:Collagen / Q000378:metabolism; D004041:Dietary Fats / Q000494:pharmacology; D004549:Elastin / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000473:pathology; D053508:Matrix Metalloproteinase 12 / Q000235:genetics; D053509:Matrix Metalloproteinase 13 / Q000235:genetics; D019278:Matrix Metalloproteinase 3 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood* / Q000235:genetics*
D001057:Apolipoproteins E; D004041:Dietary Fats; D008055:Lipids; D019715:Tissue Inhibitor of Metalloproteinase-1; D003094:Collagen; D004549:Elastin; D053509:Matrix Metalloproteinase 13; D019278:Matrix Metalloproteinase 3; D053508:Matrix Metalloproteinase 12