CX(3)CR1 deficiency confers protection from intimal hyperplasia after arterial injury

Department of Medicine, University of North Carolina at Chapel Hill, USA.
Arteriosclerosis Thrombosis and Vascular Biology (Impact Factor: 6). 10/2006; 26(9):2056-62. DOI: 10.1161/01.ATV.0000234947.47788.8c
Source: PubMed


A functional polymorphism in the chemokine receptor CX3CR1 is associated with protection from vascular diseases including coronary artery disease and internal carotid artery occlusive disease. We investigated the mechanisms by which CX3CR1 may be involved by evaluating the inflammatory response to arterial injury in CX3CR1-deficient animals.
Femoral arteries of CX3CR1-/- and wild-type (WT) mice were injured with an angioplasty guide wire. After 1, 5, 14, and 28 days, arteries were harvested and evaluated by histology, morphometry, and immunohistochemistry. Arterial injury upregulated the CX3CR1 ligand CX3CL1. In CX3CR1-/- compared with WT animals, the incidence of neointima formation was 58% lower (P=0.0017), accompanied by no difference in the area of platelet accumulation at day 1 (P=0.48) but a significant decrease in intimal monocyte infiltration at day 5 (P=0.006), vascular smooth muscle cell (VSMC) proliferation at days 5 and 14, and intimal area at day 28 (P=0.009).
In an endothelial denudation injury model, CX3CR1 deficiency protects animals from developing intimal hyperplasia as a result of decreased monocyte trafficking to the lesion. CX3CR1 deficiency decreases VSMC proliferation and intimal accumulation either directly or indirectly as a result of defective monocyte infiltration.

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    • "CCR2 is expressed on the majority of blood monocytes, other leukocytes, and a subset of T cells, mainly responding to directed cell migration toward its primary ligand MCP1 [18]. In addition, CCR2-deficient animals ex decreased susceptibility to atherosclerosis and decreased intimal hyperplasia following arterial injury [19]–[20]. Similarly, CX3CR1 is expressed on monocytes, natural killer cells, a subset of T cells, and SMCs [21]–[22]. Its ligand CX3CL1, a membrane-bound chemokine, is increased in atherosclerosis [23]. "
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    ABSTRACT: It is well documented that statins protect atherosclerotic patients from inflammatory changes and plaque instability in coronary arteries. However, the underlying mechanisms are not fully understood. Using a previously established mouse model for vulnerable atherosclerotic plaque, we investigated the effect of atorvastatin (10 mg/kg/day) on plaque morphology. Atorvastatin did not lower plasma total cholesterol levels or affect plaque progression at this dosage; however, vulnerable plaque numbers were significantly reduced in the atorvastatin-treated group compared to control. Detailed examinations revealed that atorvastatin significantly decreased macrophage infiltration and subendothelial lipid deposition, reduced intimal collagen content, and elevated collagenase activity and expression of matrix metalloproteinases (MMPs). Because vascular inflammation is largely driven by changes in monocyte/macrophage numbers in the vessel wall, we speculated that the anti-inflammatory effect of atorvastatin may partially result from decreased monocyte recruitment to the endothelium. Further experiments showed that atorvastatin downregulated expression of the chemokines monocyte chemoattractant protein (MCP)-1, chemokine (C-X3-C motif) ligand 1 (CX3CL1) and their receptors CCR2 and, CX3CR1, which are mainly responsible for monocyte recruitment. In addition, levels of the plasma inflammatory markers C-reactive protein (CRP) and tumor necrosis factor (TNF)-α were also significantly decrease in atorvastatin-treated mice. Collectively, our results demonstrate that atorvastatin can improve plaque stability in mice independent of plasma cholesterol levels. Given the profound inhibition of macrophage infiltration into atherosclerotic plaques, we propose that statins may partly exert protective effects by modulating levels of chemokines and their receptors. These findings elucidate yet another atheroprotective mechanism of statins.
    PLoS ONE 05/2014; 9(5):e97009. DOI:10.1371/journal.pone.0097009 · 3.23 Impact Factor
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    • "We have previously identified a CX3CR1 monocyte subpopulation capable of phagocytic functions typical of classical MPS as well as mural vascular smooth muscle cell-like functions that occur subsequent to CX3CL1-CX3CR1 interaction in the injured vessel wall [16], [17]. Interference with CX3CL1-CX3CR1 interaction was also observed to decrease neointima formation and atherosclerosis in murine animal models [17], [18], [19], thus implicating the CX3CL1-CX3CR1 axis in atherosclerotic plaque development. Moreover polymorphisms in CX3CR1 receptors have been associated with variability in prevalence of human atherosclerosis and coronary artery disease [19]. "
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    PLoS ONE 02/2013; 8(2):e57230. DOI:10.1371/journal.pone.0057230 · 3.23 Impact Factor
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    • "Furthermore, three distinct chemokine / chemokine receptor pairs (MCP-1 / CCR2, RANTES / CCR5, and Fractalkine / CX3CR1) have been shown to direct lesional leukocyte infiltration.[132] In addition, MCP-1 / CCR2 and Fractalkine / CX3CR1 increase expansion of neointimal SM-like cells.[133] Thus, to ultimately pharmacologically modulate the maladaptative responses in arterial remodeling, it will be essential to identify specific chemokine / chemokine receptor pairs that play specific roles in the remodeling process. "
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    03/2011; 1(1):3-16. DOI:10.4103/2045-8932.78095
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