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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 atherosclerotic plaque morphology in ApoE-/- mice.(A) Representative images of H&E staining (scale bar = 100 µm) and intimal surface/media ratio quantification in the control and atorvastatin-treated groups (p>0.05, n = 10). (B) Representative images of immunostaining for α-SMC actin (scale bar  = 100 µm) and quantification (p>0.05, n = 6). (C) Representative immunostaining for macrophages (scale bar  = 100 µm) and quantification (*p<0.05, n = 6). (D) Representative images of Oil Red O staining (scale bar  = 100 µm) and quantification (*p<0.05, n = 6). (E) Representative images of Sirius red staining (scale bar  = 100 µm) and quantification (*p<0.05, n = 6). Values are the mean ± SEM.
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pone-0097009-g001: Effect of atorvastatin (10 mg/kg/d) on atherosclerotic plaque morphology in ApoE-/- mice.(A) Representative images of H&E staining (scale bar = 100 µm) and intimal surface/media ratio quantification in the control and atorvastatin-treated groups (p>0.05, n = 10). (B) Representative images of immunostaining for α-SMC actin (scale bar  = 100 µm) and quantification (p>0.05, n = 6). (C) Representative immunostaining for macrophages (scale bar  = 100 µm) and quantification (*p<0.05, n = 6). (D) Representative images of Oil Red O staining (scale bar  = 100 µm) and quantification (*p<0.05, n = 6). (E) Representative images of Sirius red staining (scale bar  = 100 µm) and quantification (*p<0.05, n = 6). Values are the mean ± SEM.

Mentions: At 8 weeks after surgery, all of the ApoE−/− mice developed atherosclerotic lesions with vulnerable phenotypes in the LCCA as described before [11]. However, only 58.3% mice demonstrated vulnerable phenotype lesions in the atorvastatin-treated group (p<0.05), and they also exhibited decreased tendency for intraplaque hemorrhage (50% vs. 80%, p>0.05) and reduced incidence of vessel multilayer with discontinuity (25% vs. 70%, p>0.05) incidence compared with control group (Table 1). Plaque morphology was examined with histological analyses of serial sections. As shown in Figure 1A, atorvastatin-treated mice developed similar plaque areas with no difference in the intima-to-media area ratio compared to the control group (4.8±0.2 vs. 4.6±0.2, p>0.05). Similar results were observed for the mean vascular smooth muscle cell (SMC) area/intima surface area ratios (10.7±0.9% vs. 10.1±0.7%, p>0.05; Figure 1B). However, we detected significantly decreased macrophages/intima surface area ratio (21.3±1.9% vs. 34.6±1.7%, p<0.05; Figure 1C), Oil Red O staining intima surface area ratio (19.7±3.0% vs. 50.9±4.0%, p<0.05; Figure 1D), and collagen/intima surface area ratio (29.6±4.3% vs. 47.6±2.8%, p<0.05; Figure 1E) were detected in atorvastatin-treated mice.


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 atherosclerotic plaque morphology in ApoE-/- mice.(A) Representative images of H&E staining (scale bar = 100 µm) and intimal surface/media ratio quantification in the control and atorvastatin-treated groups (p>0.05, n = 10). (B) Representative images of immunostaining for α-SMC actin (scale bar  = 100 µm) and quantification (p>0.05, n = 6). (C) Representative immunostaining for macrophages (scale bar  = 100 µm) and quantification (*p<0.05, n = 6). (D) Representative images of Oil Red O staining (scale bar  = 100 µm) and quantification (*p<0.05, n = 6). (E) Representative images of Sirius red staining (scale bar  = 100 µm) and quantification (*p<0.05, n = 6). Values are the mean ± SEM.
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pone-0097009-g001: Effect of atorvastatin (10 mg/kg/d) on atherosclerotic plaque morphology in ApoE-/- mice.(A) Representative images of H&E staining (scale bar = 100 µm) and intimal surface/media ratio quantification in the control and atorvastatin-treated groups (p>0.05, n = 10). (B) Representative images of immunostaining for α-SMC actin (scale bar  = 100 µm) and quantification (p>0.05, n = 6). (C) Representative immunostaining for macrophages (scale bar  = 100 µm) and quantification (*p<0.05, n = 6). (D) Representative images of Oil Red O staining (scale bar  = 100 µm) and quantification (*p<0.05, n = 6). (E) Representative images of Sirius red staining (scale bar  = 100 µm) and quantification (*p<0.05, n = 6). Values are the mean ± SEM.
Mentions: At 8 weeks after surgery, all of the ApoE−/− mice developed atherosclerotic lesions with vulnerable phenotypes in the LCCA as described before [11]. However, only 58.3% mice demonstrated vulnerable phenotype lesions in the atorvastatin-treated group (p<0.05), and they also exhibited decreased tendency for intraplaque hemorrhage (50% vs. 80%, p>0.05) and reduced incidence of vessel multilayer with discontinuity (25% vs. 70%, p>0.05) incidence compared with control group (Table 1). Plaque morphology was examined with histological analyses of serial sections. As shown in Figure 1A, atorvastatin-treated mice developed similar plaque areas with no difference in the intima-to-media area ratio compared to the control group (4.8±0.2 vs. 4.6±0.2, p>0.05). Similar results were observed for the mean vascular smooth muscle cell (SMC) area/intima surface area ratios (10.7±0.9% vs. 10.1±0.7%, p>0.05; Figure 1B). However, we detected significantly decreased macrophages/intima surface area ratio (21.3±1.9% vs. 34.6±1.7%, p<0.05; Figure 1C), Oil Red O staining intima surface area ratio (19.7±3.0% vs. 50.9±4.0%, p<0.05; Figure 1D), and collagen/intima surface area ratio (29.6±4.3% vs. 47.6±2.8%, p<0.05; Figure 1E) were detected in atorvastatin-treated mice.

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