Broad-spectrum chemokine inhibition reduces vascular macrophage accumulation and collagenolysis consistent with plaque stabilization in mice.
BACKGROUND
A major determinant of the risk of myocardial infarction is the stability of the atherosclerotic plaque. Macrophage-rich plaques are more vulnerable to rupture, since macrophages excrete an excess of matrix-degrading enzymes over their inhibitors, reducing collagen content and thinning the fibrous cap. Several genetic studies have shown that disruption of signalling by the chemokine monocyte chemoattractant protein 1 reduced the lipid lesion area and macrophage accumulation in the vessel wall.


METHODS
We have tested whether a similar reduction in macrophage accumulation could be achieved pharmacologically by treating apolipoprotein-E-deficient mice with the chemokine inhibitor NR58-3.14.3.


RESULTS
Mice treated for various periods of time (from several days to 6 months) with NR58-3.14.3 (approximately 30 mg/kg/day) consistently had 30-40% fewer macrophages in vascular lesions, compared with mice treated with the inactive control NR58-3.14.4 or PBS vehicle. Similarly, cleaved collagen staining was lower in mice treated for up to 7 days, although this effect was not maintained when treatment time was extended to 12 weeks. The vascular lipid lesion area was unaffected by treatment, but total collagen I staining and smooth muscle cell number were both increased, suggesting that a shift to a more stable plaque phenotype had been achieved.


CONCLUSIONS
Strategies, such as chemokine inhibition, to attenuate macrophage accumulation may therefore be useful to promote stabilization of atherosclerotic plaques.
Reckless
Jill
J
Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK. jr219@cam.ac.uk
Tatalick
Laurie
L
Wilbert
Sybille
S
McKilligin
Elaine
E
Grainger
David J
DJ
D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000473:pathology*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D039481:CD11b Antigen / Q000378:metabolism; D018925:Chemokines / Q000037:antagonists & inhibitors*; D003094:Collagen / Q000737:chemistry / Q000378:metabolism*; D007150:Immunohistochemistry / Q000379:methods; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000473:pathology; D010456:Peptides, Cyclic / Q000493:pharmacokinetics / Q000494:pharmacology; D013194:Staining and Labeling
D001057:Apolipoproteins E; D039481:CD11b Antigen; D018925:Chemokines; D010456:Peptides, Cyclic; C411952:cyclo(cysteinyl-glutaminyl-isoleucyl-tryptophyl-lysyl-glutaminyl-lysyl-prolyl-aspartyl-leucyl-cysteinyl-amide); D003094:Collagen