Compensatory Enlargement and Stenosis Develop in ApoE
            <sup>−/−</sup>
            and ApoE*3-Leiden Transgenic Mice

Lutgens, Esther; Muinck, Ebo D. de; Heeneman, Sylvia; Daemen, M. J. A. P.

doi:10.1161/hq0801.093669

Cited by 24 publications

(19 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The occurrence of remodeling in the aorta and carotid arteries of ApoE Ϫ/Ϫ mice has been reported previously (Lutgens et al, 2001;Choudhury et al, 2002). The present study confirms this earlier observation and, for the first time, provides information on the temporal relationship between atherosclerosis and remodeling.…”

Section: Discussionsupporting

confidence: 92%

Probucol [4,4′-[(1-Methylethylidene)bis(thio)]bis-[2,6-bis(1,1-dimethylethyl)phenol]] Inhibits Compensatory Remodeling and Promotes Lumen Loss Associated with Atherosclerosis in Apolipoprotein E-Deficient Mice

Wu¹,

Girolamo²,

Beck³

et al. 2007

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Probucol [4,bis(thio)]bis-[2,6-bis(1,1-dimethylethyl)phenol]] was withdrawn from the United States market because it failed to inhibit atherosclerosis in human femoral arteries, yet the drug was shown subsequently to inhibit atherosclerosis in human carotid arteries, and probucol monosuccinate ester is presently being tested in a phase III clinical trial as an antiatherosclerotic compound based on its anti-inflammatory properties. Inflammatory macrophages are implicated in arterial remodeling associated with atherosclerosis, and probucol inhibits experimental atherosclerosis in part by decreasing macrophages in lesions. However, the impact of probucol on remodeling is unknown, although such knowledge could help explain why the drug's benefit on human atherosclerosis is controversial. We therefore examined the effect of probucol on remodeling of the common carotid artery in apolipoprotein E-deficient mice. We observed that during de novo atherosclerosis, plaque growth was fully compensated by expansive remodeling, such that lumen area was unaffected. Early lesions were composed almost entirely of macrophages, and their contribution to lesion area progressively decreased thereafter. Probucol significantly decreased plaque area, expression of vascular cell adhesion molecule-1, and proliferation of intimal cells, resulting in delayed macrophage accumulation in the vessel. Probucol also decreased the production and activity of matrix metalloproteinases-2 and -9, independent of the plasmin protease system, and this was associated with an inhibition of expansive remodeling, resulting in lumen loss. These studies show that probucol attenuates compensatory remodeling associated with de novo atherosclerosis, probably via its anti-inflammatory properties. Our findings suggest that lumen volume is not a suitable surrogate to assess the antiatherosclerotic activity of probucol and related drugs.Atherosclerosis is a disease characterized by the presence of heightened oxidative stress and inflammation (Stocker and Keaney, 2004), and there is increasing interest in novel compounds with antioxidant and anti-inflammatory activities as potential therapeutic antiatherosclerotic agents. AGI-1067 is one of these agents. It has antioxidant activities and selectively inhibits redox-sensitive endothelial and monocyte inflammatory gene expression in vitro, lowers low-density lipoprotein cholesterol, and decreases vascular cell adhesion molecule (VCAM)-1 expression in vivo and atherosclerosis in several animal models including apolipoprotein E-deficient (ApoE Ϫ/Ϫ ) mice (Sundell et al., 2003;Kunsch et al., 2004). AGI-1067 also decreases restenosis after percutaneous coronary intervention in humans (Tardif et al., 2003), and the compound is presently being tested as an antiatherosclerotic drug in a phase III clinical trial.AGI-1067 is a pharmacologic derivative of the antioxidant probucol. Although introduced as a lipid-lowering drug in the ABBREVIATIONS: AGI-1067, butanedioic acid, mono[4-[[1-[[3,5- 477at ASPET Journals on May 9...

show abstract

Section: Discussionsupporting

confidence: 92%

Probucol [4,4′-[(1-Methylethylidene)bis(thio)]bis-[2,6-bis(1,1-dimethylethyl)phenol]] Inhibits Compensatory Remodeling and Promotes Lumen Loss Associated with Atherosclerosis in Apolipoprotein E-Deficient Mice

Wu¹,

Girolamo²,

Beck³

et al. 2007

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…1,7,21 Several lines of evidence implicate MMP as key effectors of this process. Pasterkamp et al reported increased levels of MMP-2 and MMP-9 in expansively remodeled segments of human coronary arteries compared with constrictively remodeled segments.…”

Section: Discussionmentioning

confidence: 99%

Compensatory Vascular Remodeling During Atherosclerotic Lesion Growth Depends on Matrix Metalloproteinase-9 Activity

Lessner

Martinson

Galis

2004

ATVB

View full text Add to dashboard Cite

Objective-The compensatory arterial remodeling associated with atherosclerotic plaques is thought to rely on the activity of matrix metalloproteinases (MMP). To assess the role of MMP-9, we analyzed the effect of MMP-9 genetic deficiency on the development and remodeling of experimental atherosclerotic lesions induced in the apolipoprotein E (apoE) knockout (Ϫ/Ϫ) mouse model. Methods and Results-We analyzed remodeling parameters and cellular composition of experimental carotid artery atherosclerotic lesions in apoEϪ/Ϫ and apoEϪ/Ϫ MMP-9Ϫ/Ϫ double-knockout (DKO) mice at 0, 3, 7, and 14 days after induction by flow cessation. Morphometric image analysis of arterial tissue sections indicated that overall artery size, measured as area encompassed by the external elastic lamina, increased 3.1-fold in the apoEϪ/Ϫ mice but only 1.6-fold in the DKO mice (PϽ0.0001) by 14 days. At the same time, the net lesion area occupied by macrophages was similar. Statistical analysis indicated that the overall expansion of the artery was 2.5-fold less sensitive to macrophage content in DKO compared with apoEϪ/Ϫ mice. No compensatory increase in other gelatinolytic activities was detected in the DKO. Conclusions-MMP-9 deficiency significantly impaired compensatory vessel enlargement during carotid artery lesion development in the apoEϪ/Ϫ mouse, without altering macrophage content of lesions. (Arterioscler Thromb Vasc Biol. 2004;24:2123-2129.)Key Words: matrix metalloproteinases Ⅲ vascular remodeling Ⅲ atherosclerosis Ⅲ macrophages Ⅲ transgenic mouse models V ascular remodeling, defined as a lasting change in the diameter of a mature blood vessel, requires coordinated degradation and deposition of extracellular matrix to preserve the general architecture of the arterial wall while allowing the blood vessel to change in overall diameter. The outward remodeling of arteries provides a compensatory mechanism for preserving blood flow in the face of atherosclerotic lesion growth. 1 Advances in vascular imaging have allowed the recent appreciation of the prevalence of compensatory enlargement in coronary artery disease. 2 Because of this phenomenon, sizable plaques, which appear to be more likely to trigger acute clinical events, can elude regular angiography. 3,4 Plaque instability has been associated clinically with increased macrophage content. 5 We proposed that increased proteolytic activity, specifically caused by the action of matrix metalloproteinases (MMP), may provide a molecular mechanism for creating plaque vulnerability. See coverA substantial body of evidence suggests a key role for MMP in vascular remodeling. 6 MMP belong to a family of zinc-dependent endopeptidases capable as a class of degrading all the components of the extracellular matrix. Untimely or unbalanced MMP activity has been associated with pathological remodeling. We previously demonstrated that formation of vascular lesions in a mouse blood flow cessation model is accompanied by increased gelatinolytic activity provided by 8 By comparing the extent of geometric ...

show abstract

“…In apoE*3 Leiden and apoE knockout mice, lesion development was found associated with expansive arterial enlargement, medial thinning, and increased elastolytical activity. 41,67 These and other mouse model studies are rather descriptive, and the mechanistic link between atherosclerotic expansive remodeling and matrix degrading properties is therefore strongly suggested but yet unproven. Interventional studies using MMP inhibitors or atherosclerotic prone/protease double-knockout mice, similar to those performed in experimental models of aortic aneurysm, will be necessary.…”

Section: Expansive Atherosclerotic Remodeling: What Did We Learn Frommentioning

confidence: 99%

Expansive Arterial Remodeling: Location, Location, Location

Pasterkamp

Galis

Kleijn

2004

ATVB

118

View full text Add to dashboard Cite

Abstract-The artery is a dynamic organ capable of changing its geometry in response to atherosclerotic plaque formation.Expansion of the vessel diameter retards luminal narrowing and is considered a compensatory response. However, the expansive remodeling response is a "wolf in sheep's clothes," because expansion is associated with the presence of inflammatory cells, proteolysis, and a thrombotic plaque phenotype. The prevalence and clinical presentation of expansively remodeled lesions may differ among vascular beds. However, it is evident that all types of atherosclerotic arterial expansive lesions share the presence of inflammatory cells and subsequent protease activities. The potential role of inflammation and protease activity in the development of the different remodeling modes is discussed. Key Words: remodeling Ⅲ atherosclerosis Ⅲ toll-like receptor Ⅲ inflammation Ⅲ compensatory enlargement P laque formation has long been considered the only determinant of atherosclerotic luminal narrowing. The arterial wall, however, is not a rigid tube, but rather an organ capable of overall reshaping in response to hemodynamic, mechanical, and biochemical stimuli. For instance, the increase in the circumference of the artery can partially or totally compensate for the encroachment of the lumen caused by formation of atherosclerotic plaques or by intimal hyperplasia after arterial injury. 1-3 However, the arterial wall may also respond with constrictive remodeling, thereby aggravating the luminal narrowing response 4,5 (Figure 1).Scientific interest in the role of arterial remodeling in occlusive arterial disease boomed with the upcoming use of the visualization technique of intravascular ultrasound (IVUS). With IVUS, it became apparent just how ubiquitously remodeling can prevent plaque from encroaching on the lumen and also how failure of an expansive remodeling response accelerates luminal stenosis in de novo atherosclerosis. The role of such geometrical remodeling response in relation to plaque formation is currently appreciated but has been traditionally strongly underestimated as a causal factor for arterial occlusive disease. It has recently become clear that the geometrical change in arterial size and plaque area may equally contribute to the luminal narrowing in atherosclerotic disease 6 (Figure 2). For instance, it is possible to demonstrate that in 5% of patients eligible for coronary intervention, the plaque mass at the culprit lesion is actually smaller than that located at the angiographically normal reference site, indicating that in such lesions the degree of luminal narrowing is determined by the differences in vessel size rather than by the plaque mass. 6 In this brief review, an overview of anatomical localization and local morphology of the different remodeling modes is given. We also discuss available results of mechanistic

show abstract

Compensatory Enlargement and Stenosis Develop in ApoE ^−/− and ApoE*3-Leiden Transgenic Mice

Cited by 24 publications

References 62 publications

Probucol [4,4′-[(1-Methylethylidene)bis(thio)]bis-[2,6-bis(1,1-dimethylethyl)phenol]] Inhibits Compensatory Remodeling and Promotes Lumen Loss Associated with Atherosclerosis in Apolipoprotein E-Deficient Mice

Probucol [4,4′-[(1-Methylethylidene)bis(thio)]bis-[2,6-bis(1,1-dimethylethyl)phenol]] Inhibits Compensatory Remodeling and Promotes Lumen Loss Associated with Atherosclerosis in Apolipoprotein E-Deficient Mice

Compensatory Vascular Remodeling During Atherosclerotic Lesion Growth Depends on Matrix Metalloproteinase-9 Activity

Expansive Arterial Remodeling: Location, Location, Location

Contact Info

Product

Resources

About

Compensatory Enlargement and Stenosis Develop in ApoE −/− and ApoE*3-Leiden Transgenic Mice

Cited by 24 publications

References 62 publications

Probucol [4,4′-[(1-Methylethylidene)bis(thio)]bis-[2,6-bis(1,1-dimethylethyl)phenol]] Inhibits Compensatory Remodeling and Promotes Lumen Loss Associated with Atherosclerosis in Apolipoprotein E-Deficient Mice

Probucol [4,4′-[(1-Methylethylidene)bis(thio)]bis-[2,6-bis(1,1-dimethylethyl)phenol]] Inhibits Compensatory Remodeling and Promotes Lumen Loss Associated with Atherosclerosis in Apolipoprotein E-Deficient Mice

Compensatory Vascular Remodeling During Atherosclerotic Lesion Growth Depends on Matrix Metalloproteinase-9 Activity

Expansive Arterial Remodeling: Location, Location, Location

Contact Info

Product

Resources

About

Compensatory Enlargement and Stenosis Develop in ApoE ^−/− and ApoE*3-Leiden Transgenic Mice