Abstract 1202: Telmisartan Inhibits Cd4-positive Lymphocyte Migration Independent Of The Angiotensin-2 Type 1 Receptor Via Pparγ
Migration of CD4-positive lymphocytes into the vessel wall represents an important step in early atherogenesis. Telmisartan is an angiotensin-II type 1 receptor (AT1R) blocker with PPARgamma-activating properties. The present study examined the effect of telmisartan on CD4-positive cell migration and the role of PPARγ in this context. CD4-positive lymphocytes express both, the AT1R as well as PPARγ. Stimulation of CD4-positive lymphocytes with SDF-1 leads to a 4.5±3.4fold increase in cell migration. Pretreatment of cells with telmisartan reduces this effect in a concentration-dependent manner (from 4.5±3.4 to a 1.8±1.2fold induction at 10 μmol/L Telmisartan; p<0.05 compared to SDF-1-treated cells, n=17). In addition, telmisartan also reduced RANTES-induced cell migration, suggesting an effect independent of the chemotactic stimulus employed. Moreover, three different PPARgamma activators, rosiglitazone, pioglitazone, as well as GW1929 had similar effects, while eprosartan, a non-PPARγ-activating AT1R blocker did not affect chemokine-induced lymphocyte migration. Telmisartan’s effect 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, telmisartan inhibited f-actin formation as well as ICAM3 translocation. Blockade of the AT1R by high concentrations of eprosartan did not alter the effect of telmisartan on cell migration, while transfection of CD4-positive lymphocytes with PPARγ siRNA abolished telmisartan’s effect, suggesting that telmisartan acts via PPARgamma. Telmisartan inhibits chemokine-induced CD4-positive cell migration independent of the AT1R via PPARgamma. These data provide a novel mechanism how telmisartan modulates lymphocyte activation by its PPARgamma-activating properties.