Acute and chronic effects of troglitazone (CS-045) on isolated rat ventricular cardiomyocytes.
Freshly isolated and primary cultured adult rat cardiomyocytes were used to elucidate the mechanism of action of the new oral antidiabetic agent (+/-)-5-[4-(6-hydroxy-2, 5, 7, 8-tetramethyl-chroman-2-yl-methoxy)benzyl]-2,4-thiazolidinedione (troglitazone) on the heart. Interaction with protein kinase C (PKC) and regulation of glucose transport were evaluated as possible sites of drug action. Acute treatment (30 min) of cardiomyocytes with troglitazone did not affect the phorbolester-induced membrane association of PKC-delta and PKC-epsilon, which represent the major isoforms present in these cells. However, under these conditions the phorbolester-mediated increase in membrane associated PKC activity was inhibited by 43 +/- 4% (n = 4) without affecting the basal distribution of PKC activity. In contrast to these findings, troglitazone had no acute effect on basal or insulin-stimulated glucose transport in freshly isolated cardiomyocytes; even after 120 min treatment an unaltered release of lactate was determine in the presence of the drug. After 20 h in serum-free culture troglitazone induced a dose-dependent increase in 2-deoxyglucose uptake reaching a 40-fold stimulation at 5 mumol/l. This was paralleled by a dose-dependent increase of glucose transporter-1 (GLUT1) and GLUT4 protein expression to 320 +/- 80 and 156 +/- 15% of control, respectively. In addition, chronic exposure to troglitazone increased the GLUT4 abundance in a plasma membrane fraction about twofold. These data show that troglitazone exerts multiple effects on cardiomyocytes involving inhibition of PKC and regulation of glucose transporter expression and distribution. We suggest that an increased glucose supply may be beneficial for the diabetic heart and that modulation of PKC-activity could be relevant for improving insulin action in muscle tissue.
Bähr
M
M
Laboratory of Molecular Cardiology, Diabetes Research Institute, Düsseldorf, Germany.
Spelleken
M
M
Bock
M
M
von Holtey
M
M
Kiehn
R
R
Eckel
J
J
D019325:3-O-Methylglucose / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology*; D003600:Cytosol / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D006352:Heart Ventricles / Q000166:cytology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007106:Immune Sera / Q000276:immunology; D015151:Immunoblotting; D007527:Isoenzymes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects; D009004:Monosaccharide Transport Proteins / Q000096:biosynthesis / Q000187:drug effects / Q000276:immunology; D009124:Muscle Proteins; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D011493:Protein Kinase C / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D013997:Time Factors; D000077288:Troglitazone
D002839:Chromans; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D007106:Immune Sera; D007527:Isoenzymes; D008565:Membrane Proteins; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C495679:Slc2a1 protein, rat; C495694:Slc2a4 protein, rat; D013844:Thiazoles; D045162:Thiazolidinediones; D019325:3-O-Methylglucose; D019344:Lactic Acid; D011493:Protein Kinase C; D000077288:Troglitazone; D013755:Tetradecanoylphorbol Acetate