Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/112754
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Type: Journal article
Title: Chemokine binding protein 'M3' limits atherosclerosis in apolipoprotein E-/- mice
Author: Ravindran, D.
Ridiandries, A.
Vanags, L.
Henriquez, R.
Cartland, S.
Tan, J.
Bursill, C.
Citation: PLoS ONE, 2017; 12(3):e0173224-1-e0173224-23
Publisher: Public Library Science
Issue Date: 2017
ISSN: 1932-6203
1932-6203
Statement of
Responsibility: 
Dhanya Ravindran, Anisyah Ridiandries, Laura Z. Vanags, Rodney Henriquez, Siân Cartland, Joanne T. M. Tan, Christina A. Bursill
Abstract: Chemokines are important in macrophage recruitment and the progression of atherosclerosis. The 'M3' chemokine binding protein inactivates key chemokines involved in atherosclerosis (e.g. CCL2, CCL5 and CX3CL1). We aimed to determine the effect of M3 on plaque development and composition. In vitro chemotaxis studies confirmed that M3 protein inhibited the activity of chemokines CCL2, CCL5 and CX3CL1 as primary human monocyte migration as well as CCR2-, CCR5- and CX3CR1-directed migration was attenuated by M3. In vivo, adenoviruses encoding M3 (AdM3) or green fluorescence protein (AdGFP; control) were infused systemically into apolipoprotein (apo)-E-/- mice. Two models of atherosclerosis development were used in which the rate of plaque progression was varied by diet including: (1) a 'rapid promotion' model (6-week high-fat-fed) and (2) a 'slow progression' model (12-week chow-fed). Plasma chemokine activity was suppressed in AdM3-infused mice as indicated by significantly less monocyte migration towards AdM3 mouse plasma ex vivo (29.56%, p = 0.014). In the 'slow progression' model AdM3 mice had reduced lesion area (45.3%, p = 0.035) and increased aortic smooth muscle cell α-actin expression (60.3%, p = 0.014). The reduction in lesion size could not be explained by changes in circulating inflammatory monocytes as they were higher in the AdM3 group. In the 'rapid promotion' model AdM3 mice had no changes in plaque size but reduced plaque macrophage content (46.8%, p = 0.006) and suppressed lipid deposition in thoracic aortas (66.9%, p<0.05). There was also a reduction in phosphorylated p65, the active subunit of NF-κb, in the aortas of AdM3 mice (37.3%, p<0.0001). M3 inhibited liver CCL2 concentrations in both models with no change in CCL5 or systemic chemokine levels. These findings show M3 causes varying effects on atherosclerosis progression and plaque composition depending on the rate of lesion progression. Overall, our studies support a promising role for chemokine inhibition with M3 for the treatment of atherosclerosis.
Keywords: Chemokines; monocytes; atherosclerosis; macrophages; inflammation; aorta; lipids; plasma proteins
Rights: © 2017 Ravindran et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
RMID: 0030067900
DOI: 10.1371/journal.pone.0173224
Appears in Collections:Medicine publications

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