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.
Highlights
Statins are one of the first-line pharmacotherapeutic agents for hypercholesterolemia treatment in humans
We found that oxidative LDLinduced dendritic cell-like differentiation of macrophages was suppressed by atorvastatin through its effects on the p38 mitogenactivated protein kinase (MAPK) pathway [5]
We demonstrated that atorvastatin (10 mg/kg/d) treatment improved plaque stability by reducing inflammation and modulating chemokine and chemokine receptor expression ctrl (n = 10) ator (n = 12)
Summary
Statins are one of the first-line pharmacotherapeutic agents for hypercholesterolemia treatment in humans. During atherosclerosis initiation and progression, a common underlying cause of acute cardiovascular syndromes, such as myocardial infarction, is erosion or rupture of an unstable atherosclerotic plaque, which selectively increases circulating classical monocyte counts [2] and induces phenotypic changes that facilitate their migration into atherosclerotic lesions [3]. The inflammatory response continues as monocyte-derived macrophages, dendritic cells [4], and a subset of T cells migrate into the subendothelial area. We recently reported that atorvastatin suppressed the oxidative LDL-induced inflammatory response by inhibiting extracellular-signal-regulated kinase (ERK) phosphorylation, IkBa degradation, and cyclo-oxygenase-2 (COX-2) expression in murine macrophages. We found that oxidative LDLinduced dendritic cell-like differentiation of macrophages was suppressed by atorvastatin through its effects on the p38 mitogenactivated protein kinase (MAPK) pathway [5]. Some animal experiments have verified the effect of statins on plaque stability, little is known about the underlying in vivo mechanisms [6,7]
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