Ivabradine Reduces Chemokine-Induced CD4-Positive Lymphocyte Migration

Abstract

Aims.Migration of CD4-positive lymphocytes into the vessel wall is a critical step in atherogenesis. Recent data suggest that ivabradine, a selective I(f)-channel blocker, reduces atherosclerotic plaque formation in apolipoprotein E-deficient mice, hitherto nothing is known about the mechanism by which ivabradine modulates plaque formation. Therefore, the present study investigated whether ivabradine regulates chemokine-induced migration of lymphocytes.Methods and results.Stimulation of CD4-positive lymphocytes with SDF-1 leads to a2.0±0.1fold increase in cell migration (P<.01;n=7). Pretreatment of cells with ivabradine reduces this effect to a maximal1.2±0.1fold induction at 0.1 µmol/L ivabradine (P<.01compared to SDF-1-treated cells,n=7). The effect of ivabradine on CD4-positive lymphocyte migration was mediated through an early inhibition of chemokine-induced PI-3 kinase activity as determined by PI-3 kinase activity assays. Downstream, ivabradine inhibits activation of the small GTPase Rac and phosphorylation of the Myosin Light Chain (MLC). Moreover, ivabradine treatment reduces f-actin formation as well as ICAM3 translocation to the uropod of the cell, thus interfering with two important steps in T cell migration.Conclusion.Ivabradine inhibits chemokine-induced migration of CD4-positive lymphocytes. Given the crucial importance of chemokine-induced T-cell migration in early atherogenesis, ivabradine may be a promising tool to modulate this effect.