EXPEDITED PUBLICATION: EDITORIAL COMMENT
Pharmacological Differences of GlitazonesDoes Peroxisome Proliferator-Activated Receptor- Activation Make the Difference?*
Ulrich Kintscher, MD*
Center for Cardiovascular Research, Institute of Pharmacology, Charité–Universitätsmedizin Berlin, Berlin, Germany
* Reprint requests and correspondence: Dr. Ulrich Kintscher, Center for Cardiovascular Research, Institute of Pharmacology, Charité–Universitätsmedizin Berlin, Hessische Str. 3-4, 10115 Berlin, Germany (Email: ulrich.kintscher{at}charite.de).
Glitazones or thiazolidinediones (TZDs) are insulin-sensitizing drugs widely used in oral antidiabetic therapy (1). Currently, 2 substances, pioglitazone and rosiglitazone, are available in daily clinical practice. Both glitazones act as ligands for the nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR) and regulate its transcriptional activity. On the basis of recently published meta-analyses and trials investigating surrogate parameters for cardiovascular risk, the question has been raised whether pioglitazone and rosiglitazone exert different clinical and pharmacological actions. A controversially discussed meta-analysis reported an increased rate of myocardial infarction with rosiglitazone, although this rate was not observed in similar analysis with pioglitazone (2–4).
In addition, a previously published head-to-head comparison of both TZDs in the GLAI (Comparison of Lipid and Glycemic Effects of Pioglitazone and Rosiglitazone in Patients With Type 2 Diabetes and Dyslipidemia) study showed that pioglitazone has favorable effects on diabetic dyslipidemia, including a lowering of triglycerides and an increasing of high-density lipoprotein cholesterol when compared with rosiglitazone (5). On the basis of these data, it has been speculated that one of the underlying pharmacological mechanisms for these differences might be the transcriptional activation of the other PPAR isoform, PPAR, by glitazones in addition to PPAR activation.
In this issue of the Journal, an elegant pre-clinical and clinical study is presented by Orasanu et al. (6) characterizing PPAR activation by pioglitazone in the context of anti-inflammatory actions. A comparison between pioglitazone and rosiglitazone has been included in the pre-clinical part of this study. The authors convincingly demonstrate that pioglitazone inhibits tumor necrosis factor-alpha–induced vascular cell adhesion molecule (VCAM)-1 transcription, which is one of the major adhesion molecules involved in atherogenesis, whereas rosiglitazone has no effect. By using microvascular endothelial cells from PPAR-deficient mice, the authors prove that PPAR is required for pioglitazone's action on VCAM-1.
In consonance, pioglitazone activates the PPAR ligand binding domain (LBD) in a concentration-dependent manner, but rosiglitazone lacks this activation. Following a translational approach, Orasanu et al. (6) corroborate the PPAR-dependent suppression of VCAM-1 by pioglitazone in PPAR-deficient and wild-type mice treated with pioglitazone. Finally, they demonstrate a potential clinical relevance of their results in a clinical study in 34 diabetic patients treated either with pioglitazone or placebo for 16 weeks. Pioglitazone treatment prevented an increase in plasma soluble VCAM-1 levels. In summary, this study shows for the first time that pioglitazone-induced PPAR activation is involved in anti-inflammatory actions of this TZD.
The study by Orasanu et al. (6) doubtlessly shows that pioglitazone activates PPAR in vitro and that this activation is relevant for VCAM-1 regulation in vitro and in mice. In addition, the authors demonstrate that PPAR activation in vitro is absent with rosiglitazone. These data substantially contribute to our understanding about the pharmacology of TZDs. In vitro PPAR activation by glitazones has been previously shown by Sakamoto et al. (7). However, in the past, glitazone-mediated PPAR activation has been mainly connected to the actions of these compounds on diabetic dyslipidemia. Anti-inflammatory actions as the result of PPAR activation are novel and important mechanisms of action of pioglitazone.
The study is missing a direct comparison of the 2 TZDs in the mouse model and, more importantly, in the clinical studies (6). In their clinical study, the authors show that a plasma soluble VCAM-1 increase in the placebo group is almost completely prevented by pioglitazone treatment. Because rosiglitazone is missing in the clinical study, one has to be cautious with the interpretation of these data with respect to clinical differences among the TZDs. Anti-inflammatory actions of TZDs have been described for both compounds, including a decrease in high-sensitivity C-reactive protein, which leads to the question, how clinically relevant is the PPAR-mediated VCAM-1 regulation by pioglitazone? The answer is beyond the scope of the work of Orasanu et al. (6). Although this novel mechanism definitely contributes an additional and important part to the puzzle of pioglitazone's cardiovascular actions, the lack of a head-to-head comparison between pioglitazone and rosiglitazone in the mouse experiments and the clinical studies does not allow any major implications from these data for the understanding of pharmacological differences and the distinction of cardiovascular actions between the 2 TZDs.
From a molecular point of view, the question remains: does PPAR activation really make a difference among the glitazones? The molecular mechanisms underlying glitazone-mediated PPAR activation are complex and only partially understood. Like other nuclear hormone receptors, PPAR is in a basal state bound to so-called corepressor proteins such as nuclear receptor corepressor (8). After binding within the LBD, PPAR ligands such as TZDs induce its heterodimerization with retinoid x-receptor and its subsequent interaction with co-activators such as steroid receptor coactivators, followed by binding to PPAR response elements within target gene promoters (9).
Summarized in this concept of selective PPAR modulation, ligand-specific cofactor binding determines ligand-specific gene transcription patterns, which lead to ligand-specific biological responses (Fig. 1). More importantly, minor differences in the chemical structure of PPAR ligands such as in the structures of different glitazones result in marked differences of ligand-bound LBD conformation, which then influences cofactor binding and gene expression. Along this line, major differences in gene expression pattern between rosiglitazone and pioglitazone have been detected in adipocytes and may explain distinct biological and clinical actions (10).
Data about PPAR-cofactor binding and ligand-specific gene expression patterns in monocyte/macrophages, endothelial cells, and vascular smooth muscle cells are limited. However, one might hypothesize that ligand-specific responses based on selective PPAR modulation not only occur in one given tissue such as adipose tissue but might also be present in all tissues, including cardiovascular organs. The interactions between glitazones and the PPAR-LBD allows a wide range of ligand specificity, which subsequently results in ligand-specific responses without taking into account a potential binding to another PPAR isoform.
In summary, the transcriptional activation of PPAR by glitazones comprises only one pharmacological characteristic of ligand specificity. However, keeping the concept of selective PPAR modulation in mind, glitazone-PPAR-LBD interactions may provide an additional molecular level of ligand-specific responses. Therefore, future studies are absolutely required to focus not only on the interaction with other PPAR isoforms but also, more importantly, on glitazone-PPAR-LBD-cofactor interaction in different healthy and diseased states. Such data will be tremendously helpful to understand current differences between glitazones and to develop new ligands for the PPAR with improved clinical efficacy and less side effects.
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Footnotes
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Dr. Kintscher has received research support and speaker fees from Sanofi-Aventis, Bayer-Schering Pharma, Boehringer Ingelheim, Berlin Chemie, and Merck, Sharp & Dohme.
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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