Apolipoprotein E Knockout Mice Over-Expressing Human Tissue Inhibitor of Metalloproteinase 1 Are Protected against Aneurysm Formation but Not against Atherosclerotic Plaque Development

• Published in: Journal of vascular research Vol. 43; no. 6; pp. 493 - 501
• Main Authors: Cuaz-Pérolin, Clarisse, Jguirim, Imen, Larigauderie, Guilhem, Jlassi, Awatef, Furman, Christophe, Moreau, Martine, Chapman, M. John, Fruchart, Jean-Charles, Slimane, Mohamed Naceur, Mezdour, Hafid, Rouis, Mustapha
• Format: Journal Article
• Language: English
• Published: Basel, Switzerland Karger 01.01.2006; S. Karger AG
• Subjects: Aneurysm - pathology; Aneurysm - physiopathology; Animals; Apolipoproteins E - genetics; Arteries - metabolism; Arteries - pathology; Atherosclerosis (general aspects, experimental research); Atherosclerosis - pathology; Atherosclerosis - physiopathology; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Collagen - metabolism; Dietary Fats - pharmacology; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Elastin - metabolism; Fundamental and applied biological sciences. Psychology; Gene Expression; Humans; Lipids - blood; Macrophages - pathology; Matrix Metalloproteinase 12 - genetics; Matrix Metalloproteinase 13 - genetics; Matrix Metalloproteinase 3 - genetics; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Research Paper; Tissue Inhibitor of Metalloproteinase-1 - blood; Tissue Inhibitor of Metalloproteinase-1 - genetics; Vertebrates: cardiovascular system; Metalloproteinase inhibitors; Atherosclerotic lesions; Aneurysm; Plaque; Gene overexpression; Cardiovascular disease; Metalloendopeptidases; Vascular disease; Tissue; Apolipoprotein E; Atherosclerotic plaque; Atherosclerosis; Development; Human; Enzyme; Rodentia; Atherosclerotic lésions; Metalloproteinase inhibitors Aneurysm; Peptidases; Vertebrata; Mammalia; Mouse; Hydrolases; Inhibitor; Circulatory system; Lesion; Mutation; Formation
• ISSN: 1018-1172; 1423-0135
• DOI: 10.1159/000095309

Aims: 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. Conclusion: These data show that hTIMP-1 reduces aneurysm formation in ApoE –/– mice but does not protect them against the development of arterial lesions.