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+)=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+)=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 in this study.