The thin-cap fibroatheroma: a type of vulnerable plaque: The major precursor lesion to acute coronary syndromes

Kolodgie, Frank D.; Burke, Allen; Farb, Andrew; Gold, Herman K.; Yuan, Junying; Narula, Jagat; Finn, Aloke V.; Virmani, Renu

doi:10.1097/00001573-200109000-00006

Cited by 608 publications

(389 citation statements)

References 50 publications

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“…24 Spontaneous rupture of these predisposed lesions was rare, but administration of a vasopressor compound resulted in evidence of plaque disruption in 40% of the Ad5-CMV.p53-treated vessels. We consider the overexpression of p53 in the cap to be instrumental in inducing this plaque destabilization.…”

Section: Discussionmentioning

confidence: 99%

Induction of Atherosclerotic Plaque Rupture in Apolipoprotein E ^−/− Mice After Adenovirus-Mediated Transfer of p53

Thüsen

Vlijmen²,

Hoeben³

et al. 2002

Circulation

195

169

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Background-The presence of the tumor-suppressor gene p53 in advanced atherosclerotic plaques and the sensitivity to p53-induced cell death of smooth muscle cells isolated from these plaques have fueled speculation about the role of p53 in lesion destabilization and plaque rupture. In this study, we describe a strategy to promote (thrombotic) rupture of preexisting atherosclerotic lesions using p53-induced lesion remodeling. Methods and Results-Carotid atherogenesis was initiated in apolipoprotein E knockout mice by placement of a perivascular silastic collar. The resulting plaques were incubated transluminally with recombinant adenovirus carrying either a p53 or ␤-galactosidase (lacZ) transgene. p53 transfection was restricted to the smooth muscle cell-rich cap of the plaque and led to an increase in cap cell apoptosis 1 day after transfer. p53 overexpression resulted in a marked decrease in the cellular and extracellular content of the cap, reflected by a markedly reduced cap/intima ratio (0.21Ϯ0.04 versus 0.46Ϯ0.03, PϽ0.001). The latter is a characteristic feature of plaque vulnerability to rupture, and whereas spontaneous rupture of p53-treated lesions was rare, it was found in 40% of cases after treatment with the vasopressor compound phenylephrine (Pϭ0.003). Conclusions-We have demonstrated a potential role of p53-induced remodeling in atherosclerotic plaque destabilization.Being the first example of inducible rupture at a predefined location, this model offers a unique opportunity to delineate the processes that precede rupture and to evaluate plaque-stabilizing therapies.

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Section: Discussionmentioning

confidence: 99%

Induction of Atherosclerotic Plaque Rupture in Apolipoprotein E ^−/− Mice After Adenovirus-Mediated Transfer of p53

Thüsen

Vlijmen²,

Hoeben³

et al. 2002

Circulation

195

169

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“…Vascular smooth muscle cell (VSMC) and macrophage apoptosis, loss of extracellular matrix integrity, and inflammatory cell accumulation in the fibrous cap are thought to be important pathogenic factors leading to lesion instability (23). Attempts to produce an animal model for plaque rupture have proved difficult.…”

Section: Discussionmentioning

confidence: 99%

Participation of macrophages in atherosclerotic lesion morphology in LDLr−/− mice

Schiller

Black

Bradshaw

et al. 2004

Journal of Lipid Research

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Lyst beige (beige) mice crossed with LDL receptordeficient (LDLr ؊ / ؊ ) mice had a distinct atherosclerotic lesion morphology that was not observed in LDLr ؊ / ؊ mice. This morphology is often associated with a stable plaque phenotype. We hypothesized that macrophage expression of the beige mutation accounted for this distinct morphology. Cultured bone marrow-derived macrophages from LDLr ؊ / ؊ and beige,LDLr ؊ / ؊ mice were compared for their ability to accumulate cholesterol, efflux cholesterol, migrate in response to chemotactic stimuli through Matrigel ® -coated membranes, and express matrix metalloproteinase 9 (MMP9). No differences in cholesterol metabolism were identified. Beige,LDLr ؊ / ؊ macrophage invasion in vitro appeared to be less than LDLr ؊ / ؊ macrophage invasion but did not achieve significance. Nevertheless, tumor necrosis factor-␣ -induced MMP9 expression, secretion, and enzymatic activity of beige,LDLr ؊ / ؊ macrophages were all significantly decreased compared with those of LDLr ؊ / ؊ macrophages ( P Ͻ 0.05).

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“…Acute coronary syndrome (ACS) is provoked by disruption (rupture or erosion) of coronary atherosclerotic plaques and subsequent thrombus formation 1. Thrombi produced on disrupted plaques comprise aggregated platelets and considerable amount of fibrin; therefore, a tissue factor‐mediated coagulation pathway plays a critical role in thrombus formation that leads to the onset of ACS 2, 3, 4.…”

Section: Introductionmentioning

confidence: 99%

Indoleamine 2,3‐dioxygenase 1 in coronary atherosclerotic plaque enhances tissue factor expression in activated macrophages

Watanabe

Koyama

Yamashita

et al. 2018

Research and Practice in Thrombosis and Haemostasis

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BackgroundRecent clinical studies have found that changes in the kynurenine (Kyn) pathway of tryptophan (Trp) metabolism are associated with cardiovascular events. However, the roles of the Kyn pathway on vascular wall thrombogenicity remain unknown. Indoleamine 2,3‐dioxygenase 1 (IDO1) is a rate‐limiting enzyme of the Kyn pathway.ObjectiveThe present study aimed to localize IDO1 in human coronary atherosclerotic plaques from patients with angina pectoris and define its role in plaque thrombogenicity.MethodsImmunohistochemical methods were applied to localize IDO1 in coronary atherosclerotic plaques from patients with stable (SAP) and unstable (UAP) angina pectoris. The role of IDO1 in tissue factor (TF) expression was investigated in THP‐1 macrophages activated by interferon (IFN)γ and tissue necrosis factor (TNF)α.ResultsWe localized IDO1 mainly in CD68‐positive macrophages within atherosclerotic plaques, and in close association with TF. Areas that were immunopositive for IDO1, TF, and CD3‐positive T lymphocytes were significantly larger in plaques from patients with UAP than SAP. Macrophages activated by IFNγ and TNFα upregulated IDO1 expression, increased the Kyn/Trp ratio and enhanced TF expression and activity, but not TF pathway inhibitor expression. The IDO1 inhibitor epacadostat significantly reduced the Kyn/Trp ratio, TF expression and activity, as well as NF‐κB (p65) binding activity in activated macrophages. Inhibition of the aryl hydrocarbon receptor that binds to Kyn, also reduced Kyn‐induced TF expression in activated macrophages.ConclusionIndoleamine 2,3‐dioxygenase 1 expressed in coronary atherosclerotic plaques might contribute to thrombus formation through TF upregulation in activated macrophages.

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The thin-cap fibroatheroma: a type of vulnerable plaque: The major precursor lesion to acute coronary syndromes

Cited by 608 publications

References 50 publications

Induction of Atherosclerotic Plaque Rupture in Apolipoprotein E ^−/− Mice After Adenovirus-Mediated Transfer of p53

Induction of Atherosclerotic Plaque Rupture in Apolipoprotein E ^−/− Mice After Adenovirus-Mediated Transfer of p53

Participation of macrophages in atherosclerotic lesion morphology in LDLr−/− mice

Indoleamine 2,3‐dioxygenase 1 in coronary atherosclerotic plaque enhances tissue factor expression in activated macrophages

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The thin-cap fibroatheroma: a type of vulnerable plaque: The major precursor lesion to acute coronary syndromes

Cited by 608 publications

References 50 publications

Induction of Atherosclerotic Plaque Rupture in Apolipoprotein E −/− Mice After Adenovirus-Mediated Transfer of p53

Induction of Atherosclerotic Plaque Rupture in Apolipoprotein E −/− Mice After Adenovirus-Mediated Transfer of p53

Participation of macrophages in atherosclerotic lesion morphology in LDLr−/− mice

Indoleamine 2,3‐dioxygenase 1 in coronary atherosclerotic plaque enhances tissue factor expression in activated macrophages

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Induction of Atherosclerotic Plaque Rupture in Apolipoprotein E ^−/− Mice After Adenovirus-Mediated Transfer of p53

Induction of Atherosclerotic Plaque Rupture in Apolipoprotein E ^−/− Mice After Adenovirus-Mediated Transfer of p53