Raised soluble P-selectin moderately accelerates atherosclerotic plaque progression.
Soluble P-selectin (sP-selectin), a biomarker of inflammatory related pathologies including cardiovascular and peripheral vascular diseases, also has pro-atherosclerotic effects including the ability to increase leukocyte recruitment and modulate thrombotic responses in vivo. The current study explores its role in progressing atherosclerotic plaque disease. Apoe-/- mice placed on a high fat diet (HFD) were given daily injections of recombinant dimeric murine P-selectin (22.5 µg/kg/day) for 8 or 16 weeks. Saline or sE-selectin injections were used as negative controls. In order to assess the role of sP-selectin on atherothrombosis an experimental plaque remodelling murine model, with sm22α-hDTR Apoe-/- mice on a HFD in conjunction with delivery of diphtheria toxin to induce targeted vascular smooth muscle apoptosis, was used. These mice were similarly given daily injections of sP-selectin for 8 or 16 weeks. While plaque mass and aortic lipid content did not change with sP-selectin treatment in Apoe-/- or SM22α-hDTR Apoe-/- mice on HFD, increased plasma MCP-1 and a higher plaque CD45 content in Apoe-/- HFD mice was observed. As well, a significant shift towards a more unstable plaque phenotype in the SM22α-hDTR Apoe-/- HFD mice, with increased macrophage accumulation and lower collagen content, leading to a lower plaque stability index, was observed. These results demonstrate that chronically raised sP-selectin favours progression of an unstable atherosclerotic plaque phenotype.
Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
Kevin J
KJ
Woollard
Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
Natalie G
NG
Lumsden
Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
Karen L
KL
Andrews
Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
Andrea
A
Aprico
Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
Emma
E
Harris
Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
Jennifer C
JC
Irvine
Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
Ann-maree
AM
Jefferis
Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
Lu
L
Fang
Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
Peter
P
Kanellakis
Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
Alex
A
Bobik
Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
Jaye P F
JP
Chin-Dusting
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D004041:Dietary Fats / Q000009:adverse effects* / Q000494:pharmacology; D004195:Disease Models, Animal; D017493:Leukocyte Common Antigens / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D019007:P-Selectin / Q000097:blood* / Q000235:genetics; D058226:Plaque, Atherosclerotic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
D001057:Apolipoproteins E; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D004041:Dietary Fats; D019007:P-Selectin; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse