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

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.

Ligation of Macrophage Fcγ Receptors Recapitulates the Gene Expression Pattern of Vulnerable Human Carotid Plaques

“…TIMP-1 message was significantly higher in proximal vs distal regions (Figures 2, 4) and TIMP-1 protein localized to macrophages (Figure 7). This is consistent with reports that TIMP-1 overexpression does not alter plaque stability [20]. TIMP-4 mRNA was low and similar in both regions (Figure 2).…”

Let-7 in Cardiovascular Diseases, Heart Development and Cardiovascular Differentiation from Stem Cells

“…In in vivo studies, let-7g levels were found reduced both in high-fat diet mice and hypercholesterolemia humans, in accordance with in vitro results [60]. Let-7d and let-7i levels are down-regulated in CAD patients [27,64], and let-7s are up-regulated in patients suffering atherosclerotic abdominal aortic aneurysm (AAA) [65].…”

Collagens in the progression and complications of atherosclerosis

“…When transgenic mice overexpressing TIMP-1 were cross-bred with ApoE-null mice, there was no difference in lesion area compared to ApoE-null controls. 108 Two independent studies of mice with targeted deletion of TIMP-1 on the ApoE-null background also report contradictory results; plaque formation was either decreased 109 or not changed. 110 By contrast, overexpression of TIMP-2 by systemic injection of adenovirus inhibited plaque growth by decreasing macrophage invasion; however, SMC number and collagen and elastin content were increased.…”