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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 plasma inflammatory markers TNF-α and CRP in ApoE-/- mice.Blood was collected 8 weeks after isosmotic saline or atorvastatin administration. Data represent the mean ± SEM of six ELISA experiments. *p<0.05 compared with control.
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pone-0097009-g004: Effect of atorvastatin (10 mg/kg/d ) on plasma inflammatory markers TNF-α and CRP in ApoE-/- mice.Blood was collected 8 weeks after isosmotic saline or atorvastatin administration. Data represent the mean ± SEM of six ELISA experiments. *p<0.05 compared with control.

Mentions: Finally, we verified the anti-inflammatory effect of atorvastatin by measuring inflammatory markers in plasma. As shown in Figure 4, the mean TNF-α level was significantly decreased in the atorvastatin-treated group compared to control (1.0±0.04 vs. 1.2±0.04 ng/ml, p<0.01). Plasma hsCRP levels showed a similar trend; a markedly reduced concentration was observed in the atorvastatin-treated group compared with the control group (0.81±0.14 vs. 1.37±0.16 ng/ml, p<0.05).


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 plasma inflammatory markers TNF-α and CRP in ApoE-/- mice.Blood was collected 8 weeks after isosmotic saline or atorvastatin administration. Data represent the mean ± SEM of six ELISA experiments. *p<0.05 compared with control.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0097009-g004: Effect of atorvastatin (10 mg/kg/d ) on plasma inflammatory markers TNF-α and CRP in ApoE-/- mice.Blood was collected 8 weeks after isosmotic saline or atorvastatin administration. Data represent the mean ± SEM of six ELISA experiments. *p<0.05 compared with control.
Mentions: Finally, we verified the anti-inflammatory effect of atorvastatin by measuring inflammatory markers in plasma. As shown in Figure 4, the mean TNF-α level was significantly decreased in the atorvastatin-treated group compared to control (1.0±0.04 vs. 1.2±0.04 ng/ml, p<0.01). Plasma hsCRP levels showed a similar trend; a markedly reduced concentration was observed in the atorvastatin-treated group compared with the control group (0.81±0.14 vs. 1.37±0.16 ng/ml, p<0.05).

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