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

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Abstract
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.

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