title: Troglitazone, but not rosiglitazone, inhibits Na/H exchange activity and proliferation of macrovascular endothelial cells.
abstract: Diabetes is associated with a high level of mortality due to cardiovascular disease resulting from accelerated coronary artery atherosclerosis. A current focus for investigation of atherosclerotic mechanisms is the vascular endothelium since physical or functional injury may represent an initiating step for atherogenesis. Thiazolidinediones (TZDs) are the newest class of drugs for the treatment of insulin resistance and its metabolic consequences; they are peroxisome proliferator-activating receptor (PPAR)-gamma ligands that act as insulin-sensitizing agents. We are interested in the contribution of direct vascular actions to the clinical utility of these agents. We investigated the effect troglitazone and rosiglitazone on endothelial cell proliferation in low- and high-glucose media and further explored their action on the ubiquitous membrane transport system, the Na/H exchanger (NHE), which has been implicated in regulating the growth of vascular cells. Experiments were conducted in cultured bovine aortic endothelial cells (BAECs). Cell proliferation was assessed by cell counting, and NHE activity was determined in cells loaded with the pH-sensitive fluorescent dye, 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein, acetoxymethyl ester (BCECF-AM). Troglitazone caused a dose-dependent inhibition of endothelial cell proliferation with approximately 50% inhibition at 10 microM. Troglitazone inhibited endothelial cell proliferation with similar potency under low- (5 mM) and high-glucose (25 mM) concentrations. Rosiglitazone had no significant effect on endothelial cell proliferation at concentrations of up to 100 microM under low- or high-glucose concentrations. The NHE inhibitor, 3-metlylsulfonyl-4-piperidinobenzoyl guanidine (HOE 694), caused dose dependent inhibition of BAEC proliferation, which was independent of the media glucose concentration. Acute exposure of cells to troglitazone (10 microM) and rosiglitazone (30 microM) during recovery from acidosis showed slight but significant (P<.05) inhibition of NHE activity by troglitazone, but no significant (P>.05) effect by rosiglitazone. Exposure of cells to either drug for 24 h revealed no chronic regulation of NHE activity. Our data demonstrate that troglitazone has similar actions in endothelial cells as in vascular smooth muscle. The absence of rosiglitazone effects, a more potent PPAR-gamma activator, suggests that the observed actions of troglitazone may be at least partially independent of PPAR-gamma. The effects of troglitazone and rosiglitazone on endothelial cell proliferation and NHE activity, although contrasting, are consistent with a central signalling role of this transporter in cell proliferation.
authors.affiliation: Cell Biology of Diabetes Laboratory, Baker Medical Research Institute, P.O. Box 6492, Victoria, Melbourne 8008, Australia.
authors.forename: S T
authors.initials: ST
authors.lastname: de Dios
authors.forename: K M
authors.initials: KM
authors.lastname: Hannan
authors.forename: R J
authors.initials: RJ
authors.lastname: Dilley
authors.forename: M A
authors.initials: MA
authors.lastname: Hill
authors.forename: P J
authors.initials: PJ
authors.lastname: Little
mesh_terms: D000199:Actins / Q000032:analysis; D000818:Animals; D001011:Aorta; D015415:Biomarkers / Q000032:analysis; D002417:Cattle; D002455:Cell Division / Q000187:drug effects*; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007700:Kinetics; D019001:Nitric Oxide Synthase / Q000032:analysis; D052250:Nitric Oxide Synthase Type III; D000077154:Rosiglitazone; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013450:Sulfones / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D000077288:Troglitazone
chemical_list: D000199:Actins; D015415:Biomarkers; D002839:Chromans; D006146:Guanidines; D007004:Hypoglycemic Agents; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; D013844:Thiazoles; D045162:Thiazolidinediones; D000077154:Rosiglitazone; C074107:3-methylsulfonyl-4-piperidinobenzoyl guanidine; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D000077288:Troglitazone; D005947:Glucose