The Non-Genomic Effects Of The PPAR-γ Ligand Rosiglitazone On Intracellular Calcium Concentrations In Mammalian Monocytic And Smooth Muscle Cells
University of Wales
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Thiazolidinediones such as rosiglitazone are used in the treatment of Type-2 Diabetes, and are ligands for peroxisome proliferator-activated receptor-gamma (PPARγ), a ligand-activated transcription factor that regulates expression of genes involved in glucose and lipid metabolism. However, rosiglitazone is known to exert PPARγ-independent effects alongside its classical receptor-dependent effects. This study investigated the PPARγ-independent effects of rosiglitazone on intracellular calcium (Ca2+i) signalling in cultured monocytic and vascular smooth muscle cells Rosiglitazone rapidly (5-30min) inhibited the Ca2+ sequestration activity of the ER-resident Ca2+ pump enzyme SERCA2b in a dose-dependent manner (IC50~2μM). 10μM Rosiglitazone triggered rapid increases in [Ca2+]i; however, restoration to basal levels occurred within 72h. Consequently, cell viability was not adversely affected by rosiglitazone treatment. Initiation of the unfolded protein response (UPR) was identified as the mechanism underpinning rosiglitazone's Ca2+ homeostatic restorative properties. Rosiglitazone induced alternate splicing of the UPR transcription factor XBP-1, which led to increased mRNA and protein expression of SERCA2b (shown via bioinformatics analysis to be a UPR target gene), and increased ER Ca2+-ATPase activity in rosiglitazone-treated cells. In tissue (rabbit aortic ring) samples, 10μM rosiglitazone induced transient (within 1h) non-significant losses in vasorelaxatory sensitivity to sodium nitroprusside, but extended treatment (4-24h) increased sensitivity beyond that of vehicle-treated samples. Thus, at cell and tissue levels, this data suggests that rosiglitazone initially causes increased [Ca2+]i due to inhibition of SERCA2b, but extended incubation induces - via upregulation of UPR target genes - the restoration of Ca2+ homeostasis, and possibly even improvements in function in some contexts. Clearly, the data presented in this in vitro study must be treated tentatively, and more research is needed before these potentially beneficial effects can be firmly identified as being clinically significant. Nevertheless, the data obtained here may constitute preliminary evidence that, alongside its PPARy-dependent effects, rosiglitazone may exert functional improvements on the vasculature.
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