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Atorvastatin improves plaque stability in ApoE-knockout mice by regulating chemokines and chemokine receptors.

Nie P, Li D, Hu L, Jin S, Yu Y, Cai Z, Shao Q, Shen J, Yi J, Xiao H, Shen L, He B - PLoS ONE (2014)

Bottom Line: 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.These findings elucidate yet another atheroprotective mechanism of statins.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.

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.

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Effect of atorvastatin (10 mg/kg/d)on expression levels of intimal chemokines and their receptors e on peripheral blood monocytes in ApoE-/- mice.(A) Representative images of immunostaining for MCP-1 and CX3CL1 (scale bar  = 100 µm) and quantification in the control and atorvastatin-treated groups (*p<0.05, n = 6). (B) Representative FACS analysis for monocytes with double-immunofluorescent labeling for CCR2 and CX3CR1. Data represent the mean ± SEM of the percentage of marker-positive cells from six experiments. *p<0.05 compared with control.
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pone-0097009-g003: Effect of atorvastatin (10 mg/kg/d)on expression levels of intimal chemokines and their receptors e on peripheral blood monocytes in ApoE-/- mice.(A) Representative images of immunostaining for MCP-1 and CX3CL1 (scale bar  = 100 µm) and quantification in the control and atorvastatin-treated groups (*p<0.05, n = 6). (B) Representative FACS analysis for monocytes with double-immunofluorescent labeling for CCR2 and CX3CR1. Data represent the mean ± SEM of the percentage of marker-positive cells from six experiments. *p<0.05 compared with control.

Mentions: Because we observed changes in the numbers of macrophages but not SMCs in atorvastatin-treated mice, we considered that improved plaque stability might explain the decrease in macrophage quantity compared to control mice. Then, we asked whether this resulted from atorvastatin treatment interrupting monocyte infiltration into atherosclerotic plaques. As expected from the intimal immunofluorescent labeling shown in Figure 3A, chemokine MCP-1 and CX3CL1 expression levels were both significantly decreased by atorvastatin (10.9±1.0% vs. 23.0±2.1% p<0.05 and 15.0±1.4% vs. 26.4±1.8% p<0.05, respectively). At the same time, mice peripheral blood monocytes identified as double-labeled for CD115 and Ly-6C antigens were analyzed by FACS. The expression levels of the corresponding chemokine receptors CCR2 and CX3CR1 were also inhibited in atorvastatin-treated mice (91.5±0.7% vs. 97.1±1.0% p<0.05 and 30.0±1.6% vs. 38.5±1.8% p<0.05, respectively, Figure 3B). And there was a significant association between reduced levels of neointimal chemokines and decreased macrophage quantity, lipid deposition, collagenase activity, as well as increased collagen content (p<0.05, see Table S2 in the File S1).


Atorvastatin improves plaque stability in ApoE-knockout mice by regulating chemokines and chemokine receptors.

Nie P, Li D, Hu L, Jin S, Yu Y, Cai Z, Shao Q, Shen J, Yi J, Xiao H, Shen L, He B - PLoS ONE (2014)

Effect of atorvastatin (10 mg/kg/d)on expression levels of intimal chemokines and their receptors e on peripheral blood monocytes in ApoE-/- mice.(A) Representative images of immunostaining for MCP-1 and CX3CL1 (scale bar  = 100 µm) and quantification in the control and atorvastatin-treated groups (*p<0.05, n = 6). (B) Representative FACS analysis for monocytes with double-immunofluorescent labeling for CCR2 and CX3CR1. Data represent the mean ± SEM of the percentage of marker-positive cells from six experiments. *p<0.05 compared with control.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4016207&req=5

pone-0097009-g003: Effect of atorvastatin (10 mg/kg/d)on expression levels of intimal chemokines and their receptors e on peripheral blood monocytes in ApoE-/- mice.(A) Representative images of immunostaining for MCP-1 and CX3CL1 (scale bar  = 100 µm) and quantification in the control and atorvastatin-treated groups (*p<0.05, n = 6). (B) Representative FACS analysis for monocytes with double-immunofluorescent labeling for CCR2 and CX3CR1. Data represent the mean ± SEM of the percentage of marker-positive cells from six experiments. *p<0.05 compared with control.
Mentions: Because we observed changes in the numbers of macrophages but not SMCs in atorvastatin-treated mice, we considered that improved plaque stability might explain the decrease in macrophage quantity compared to control mice. Then, we asked whether this resulted from atorvastatin treatment interrupting monocyte infiltration into atherosclerotic plaques. As expected from the intimal immunofluorescent labeling shown in Figure 3A, chemokine MCP-1 and CX3CL1 expression levels were both significantly decreased by atorvastatin (10.9±1.0% vs. 23.0±2.1% p<0.05 and 15.0±1.4% vs. 26.4±1.8% p<0.05, respectively). At the same time, mice peripheral blood monocytes identified as double-labeled for CD115 and Ly-6C antigens were analyzed by FACS. The expression levels of the corresponding chemokine receptors CCR2 and CX3CR1 were also inhibited in atorvastatin-treated mice (91.5±0.7% vs. 97.1±1.0% p<0.05 and 30.0±1.6% vs. 38.5±1.8% p<0.05, respectively, Figure 3B). And there was a significant association between reduced levels of neointimal chemokines and decreased macrophage quantity, lipid deposition, collagenase activity, as well as increased collagen content (p<0.05, see Table S2 in the File S1).

Bottom Line: 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.These findings elucidate yet another atheroprotective mechanism of statins.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.

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.

Show MeSH
Related in: MedlinePlus