Systematic Review and Meta-Analysis of the Effect of Statins on Circulating E-Selectin, L-Selectin, and P-Selectin

The pleiotropic effects of statins might involve preventing inflammatory cell adhesion to the endothelium, which is a critical step in the pathogenesis of atherosclerosis. We conducted a systematic review and meta-analysis of the effects of statins on the circulating cell adhesion molecules E-Selectin, L-Selectin, and P-Selectin. A literature search was conducted in PubMed, Web of Science, and Scopus, from inception to July 2021. Risk of bias and certainty of evidence were assessed using the Joanna Briggs Institute Critical Appraisal Checklist and GRADE, respectively. In 61 studies, statins significantly reduced P-selectin (standard mean difference, SMD = −0.39, 95% CI −0.55 to −0.22, p < 0.001; moderate certainty of evidence), L-selectin (SMD = −0.49, 95% CI −0.89 to −0.10, p = 0.014; very low certainty of evidence), and E-Selectin (SMD = −0.73, 95% CI −1.02 to −0.43, p < 0.001; moderate certainty of evidence), independently of baseline lipid profile and other study and patient characteristics. The corresponding pooled SMD values in sensitivity analysis were not substantially altered when individual studies were sequentially removed. Simvastatin had a significant lowering effect on both P-selectin and E-selectin. Therefore, statins significantly reduce circulating selectins. Further studies are required to investigate whether selectin lowering mediates cardiovascular risk reduction with these agents. (PROSPERO registration number: CRD42021282778).

Interactions through L-selectin between leukocytes and adherent leukocytes nucleate rolling adhesions on selectins and VCAM-1 in shear flow.

We demonstrate an additional step and a positive feedback loop in leukocyte accumulation on inflamed endothelium. Leukocytes in shear flow bind to adherent leukocytes through L-selectin/ligand interactions and subsequently bind downstream and roll on inflamed endothelium, purified E-selectin, P-selectin, L-selectin, VCAM-1, or peripheral node addressin. Thus adherent leukocytes nucleate formation of strings of rolling cells and synergistically enhance leukocyte accumulation. Neutrophils, monocytes, and activated T cell lines, but not peripheral blood T lymphocytes, tether to each other through L-selectin. L-selectin is not involved in direct binding to either E- or P-selectin and is not a major counterreceptor of endothelial selectins. Leukocyte-leukocyte tethers are more tolerant to high shear than direct tethers to endothelial selectins and, like other L-selectin-mediated interactions, require a shear threshold. Synergism between leukocyte-leukocyte and leukocyte-endothelial interactions introduces novel regulatory mechanisms in recruitment of leukocytes in inflammation.