The PPAR gamma 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 Ca2+ ATPase SERCA2b in monocytic cells (IC50 = 1.88 mu M; p < 0.05), thereby disrupting short-term Ca2+ homeostasis (resting [Ca2+](cyto) = 121.2 +/- 2.9% basal within 1 h; p < 0.05). However, extended Rosiglitazone treatment (72 h) induced dose-dependent SER-CA2b up-regulation, and restored calcium homeostasis, in monocytic cells (SERCA2b mRNA: 138.7 +/- 5.7% basal (1 mu M)/ 215.0 +/- 30.9% basal (10 mu M); resting [Ca2+](cyto) = 97.3 +/- 8.3% basal (10 mu M)). As unfavourable cardiovascular outcomes, possibly related to disrupted cellular Ca2+ 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 PPAR gamma-dependent effects (1 mu M: 152.5 +/- 14.9% basal; 10 mu M: 136.1 +/- 5.1% basal (p < 0.05 for 1 mu M vs. 10 mu M)). Thus, we conclude that Rosiglitazone can exert PPAR-gamma-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. (C) 2007 Elsevier Inc. All rights reserved.