Rosiglitazone transiently disturbs calcium homeostasis in monocytic cells.
The PPARgamma agonist Rosiglitazone exerts anti-hyperglycaemic effects by regulating the long-term expression of genes involved in metabolism, differentiation and inflammation. In the present study, Rosiglitazone treatment rapidly inhibited (5-30 min) the ER Ca(2+) ATPase SERCA2b in monocytic cells (IC(50)=1.88 microM; p<0.05), thereby disrupting short-term Ca(2+) homeostasis (resting [Ca(2+)](cyto)=121.2+/-2.9% basal within 1h; p<0.05). However, extended Rosiglitazone treatment (72 h) induced dose-dependent SERCA2b up-regulation, and restored calcium homeostasis, in monocytic cells (SERCA2b mRNA: 138.7+/-5.7% basal (1 microM)/215.0+/-30.9% basal (10 microM); resting [Ca(2+)](cyto)=97.3+/-8.3% basal (10 microM)). As unfavourable cardiovascular outcomes, possibly related to disrupted cellular Ca(2+) homeostasis, have been linked to Rosiglitazone, this effect may be of clinical interest. In contrast, in PPRE-luciferase reporter-gene assays, Rosiglitazone induced non-dose-dependent PPARgamma-dependent effects (1 microM: 152.5+/-4.9% basal; 10 microM: 136.1+/-5.1% basal (p<0.05 for 1 microM vs. 10 microM)). Thus, we conclude that Rosiglitazone can exert PPARgamma-independent non-genomic effects, such as the SERCA2b inhibition seen here, but that long-term Rosiglitazone treatment did not perturb resting [Ca](cyto) in this study.
Centre for Biomedical Sciences, Cardiff School of Health Sciences, University of Wales Institute Cardiff, Cardiff CF5 2YB, UK.
J
J
Caddy
N
N
Singh
L
L
Atkin
M
M
Ahluwalia
A
A
Roberts
D
D
Lang
A W
AW
Thomas
R
R
Webb
D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D000077154:Rosiglitazone; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000187:drug effects / Q000378:metabolism*; D045162:Thiazolidinediones / Q000008:administration & dosage*
D045162:Thiazolidinediones; D000077154:Rosiglitazone; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium