Given the safety concerns expressed over negative cardiovascular outcomes resulting from the clinical use of rosiglitazone, and the view that rosiglitazone exerts PPAR gamma-independent effects alongside its insulin-sensitising PPAR gamma-dependent effects, we hypothesised that rosiglitazone may trigger Unfolded Protein Responses (UPRs) due to disruptions in [Ca2+](i) homeostasis within two cardiovascular cell types: monocytic (MM6) and vascular smooth muscle (A7r5) cells.In microsomal samples derived from both cell types, pre-incubation with rosiglitazone rapidly (30 min) brought about concentration-dependent PPAR gamma-independent inhibition of Ca(2+)ATPase activity (IC50 similar to 2 mu M). Fluo-3 fluorimetric data demonstrated in intact cells that 1 h treatment with 1 or 10 mu M rosiglitazone caused Ca2+ ions to leak into the cytoplasm. Gene expression analysis showed that within 4 h of rosiglitazone exposure, the UPR transcription factor XBP-1 was activated (likely due to corresponding ER Ca2+ depletion), and the UPR target genes BiP and SERCA2b were subsequently upregulated within 24-72 h.After 72 h 1 or 10 mu M rosiglitazone treatment, microsomal Ca(2+)ATPase activity increased to >2-fold of that seen in control microsomes, while [Ca2+](i) returned to basal, indicating that UPR-triggered SERCA2b upregulation was responsible for enhanced enzymatic Ca2+ sequestration within the ER. This appeared to be sufficient to replenish ER Ca2+ stores and restore normal cell physiology, as cell viability levels were not decreased due to rosiglitazone treatment throughout a 2-week study.Thus, incubation with 1-10 mu M rosiglitazone triggers the UPR, but does not prove cytotoxic, in cells of the cardiovascular system. This observation provides an important contribution to the current debate over the use of rosiglitazone in the clinical treatment of Type-2 Diabetes. (c) 2010 Elsevier Inc. All rights reserved.

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.

AnaesthesiaVolume 45, Issue 12 p. 1102-1102 Free Access Inadequate reversal J. Caddy, J. Caddy Pontefract General Infirmary, Pontefract, West Yorkshire WF8 1PLSearch for more papers by this author J. Caddy, J. Caddy Pontefract General Infirmary, Pontefract, West Yorkshire WF8 1PLSearch for more papers by this author First published: December 1990 https://doi.org/10.1111/j.1365-2044.1990.tb14944.xAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume45, Issue12December 1990Pages 1102-1102 RelatedInformation