CX(3)CR1 deficiency confers protection from intimal hyperplasia after arterial injury
ABSTRACT 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.
SourceAvailable from: Linghong Shen[Show abstract] [Hide abstract]
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 · 3.53 Impact Factor
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ABSTRACT: Background An association between genetic factors and arteriosclerosis exists for chemokine receptor polymorphisms, CCR2 and two tightly linked SNPs of the CX3CR1, coding for positions 249 and 290 of the receptor. Aim of the study To describe frequency of I249V and M290T alleles in HIV-1 infected patients in the context of cardiovascular diseases (CVDs). Material and methods 168 HIV-1 infected Caucasians aged 23-66 ys (28.0% women and 72.0% men) were included into the study. QIAamp DNA Blood mini kit and was used to extract genomic DNA from blood. To assess the distribution of single nucleotide polymorphisms PCR-RFLP protocols were used. For all reaction products electrophoresis in the 2,5 % agarose gel stained with ethidium bromide was performed. Results were visualized in the UV light under transilluminator and recorded with polaroid camera. Results For the 249 site the I/I allele of CX3CR1 was present in 17(10,1 %) patients. For the second assessed variant in position 290, 102 individuals (60,7%) were carrying a T/T homozygous genotype, and 11 (6,6%) patients homozygous for the M/M genotype. Patients homozygous for both I/I and M/M genotypes had no history of CVDs. Cardiovascular events were diagnosed in 8 patients. No protective homozygous I/I and M/M genotypes were found among these patients. Conclusions No research on the influence of these polymorphisms on the CVDs incidence among HIV patients was published – this is a preliminary report on this matter. As protective I/I and M/M genotypes were not present in a group with these complications, further study has to be performed to obtain conclusive results. Basing on fraktalkine polymorphism genotyping, patients may be treated with wider spectrum of antiretrovirals, so such analyses may become a useful tool for clinical practice.01/2007; 6(1):28-31. DOI:10.1016/S1730-1270(10)60039-2