Telmisartan inhibits CD4-positive lymphocyte migration independent of the angiotensin type 1 receptor via peroxisome proliferator-activated receptor-gamma.
Migration of CD4-positive lymphocytes into the vessel wall represents an important step in early atherogenesis. Telmisartan is an angiotensin type 1 receptor (AT1R) blocker with peroxisome proliferator-activated receptor (PPAR)-gamma-activating properties. The present study examined the effect of telmisartan on CD4-positive cell migration and the role of PPARgamma in this context. CD4-positive lymphocytes express both the AT1R and PPARgamma. Stimulation of CD4-positive lymphocytes with stromal cell-derived factor (SDF)-1 leads to a 4.1+/-3.1-fold increase in cell migration. Pretreatment of cells with telmisartan reduces this effect in a concentration-dependent manner to a maximal 1.6+/-0.7-fold induction at 10 mumol/L of telmisartan (P<0.01 compared with SDF-1-treated cells; n=22). Three different PPARgamma activators, rosiglitazone, pioglitazone, and GW1929, had similar effects, whereas eprosartan, a non-PPARgamma-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 phosphatidylinositol 3-kinase activity. Downstream, telmisartan inhibited F-actin formation, as well as intercellular adhesion molecule-3 translocation. Transfection of CD4-positive lymphocytes with PPARgamma small interfering RNA abolished telmisartan's effect on migration, whereas blockade of the AT1R had no such effect. Telmisartan inhibits chemokine-induced CD4-positive cell migration independent of the AT1R via PPARgamma. These data provide a novel mechanism to explain how telmisartan modulates lymphocyte activation by its PPARgamma-activating properties.
D000199:Actins / Q000037:antagonists & inhibitors; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D015703:Antigens, CD / Q000378:metabolism; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D001565:Benzoates / Q000008:administration & dosage / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D047495:PPAR gamma / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D000077333:Telmisartan
D000199:Actins; D047228:Angiotensin II Type 1 Receptor Blockers; D015703:Antigens, CD; D001562:Benzimidazoles; D001565:Benzoates; D015815:Cell Adhesion Molecules; D054377:Chemokine CXCL12; C483616:ICAM3 protein, human; D047495:PPAR gamma; D000081082:Phosphoinositide-3 Kinase Inhibitors; D044140:Receptor, Angiotensin, Type 1; D000077333:Telmisartan