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 mg/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 sm22 alpha-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 SM22 alpha-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 SM22 alpha-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.