Atorvastatin Improves Plaque Stability in ApoE-Knockout Mice by Regulating Chemokines and Chemokine Receptors

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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“…The authors of a recent study using apolipoprotein E-knockout mice found that the addition of Atorvastatin to a high fat diet decreased LDL cholesterol levels in the blood, as expected, but also decreased the GGT expression in the plaque at the same time [150]. To us, this suggests that there is a reduced need for GGT to promote sulfate synthesis because there is insufficient cholesterol in the blood to be conjugated with it to form cholesterol sulfate.…”

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“…Immunohistochemistry staining was performed as described (Jin et al, 2012;Nie et al, 2014). Briefly, frozen sections were fixed with 4% paraformaldehyde at 4°C for 20 min, permeabilized with 0.2% Triton X-100 for 10 min at room temperature and blocked with 5% BSA IL-6, MMP13, TNF-α, and CCL2) were normalized to β-actin.…”

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“…Classically, it has been believed that the site of this anti‐inflammatory action is on the blood‐borne side of the arterial wall, i.e. statins suppress the inflammation that results from hypercholesterolaemia and the imbibing of oxidized lipoproteins across a dysfunctional coronary artery endothelium . However, in recent years, investigators have proposed that the primary site of the anti‐inflammatory benefit of statins may be in the adventitia, specifically in the perivascular adipose tissue that surrounds the coronary arteries .…”

“…statins suppress the inflammation that results from hypercholesterolaemia and the imbibing of oxidized lipoproteins across a dysfunctional coronary artery endothelium. 28,29 However, in recent years, investigators have proposed that the primary site of the anti-inflammatory benefit of statins may be in the adventitia, specifically in the perivascular adipose tissue that surrounds the coronary arteries. 30,31 The distribution of epicardial fat is focally asymmetric, and intriguingly, focal obstructive lesions develop in the coronary arterial segments that are immediately adjacent to areas of epicardial fat with the greatest thickness.…”