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[摘要]：Peroxisome proliferator-activator receptors (PPARs) are now known as members of the nuclear hormone-receptor superfamily of ligand-activated transcription factors that regulate gene expression in response to nutritional and physiological stimuli. PPAR gamma plays a crucial role in glucose homeostasis and it is involved in the regulation of lipid metabolism and adipocyte differentiation and function. From all the PAAR gamma ligands, the thiazolidindiones (TZDs) are of most clinical importance. Rosiglitazone and pioglitazonehave been largely used so far in the clinical practice. They provide similar effects on glycemic control, as well as a range of similar adverse effects, such as weight gain, fluid retention, and increased risk of hearth failure, which seem to be PPAR gamma mediated. Interestingly, they differ on their effect on lipid and cardiovascular safety profile, indicating a PPAR gamma-independent mechanism. Indeed, rosiglitazone was recently withdrawn in Europe and its use has been restricted in USA as a consequence of increased risk of cardiovascular events in type 2 diabetic patients. This review is focused on the cardiovascular effects of rosiglitazone and pioglitazone as representative members of PPAR gamma ligands, because they were widely evaluated in many clinical trials and experimental studies and data obtained from these studies are relevant from medicinal chemistry and clinical pharmacology point of view. Finally, an overview on the development of selective PPAR gamma modulators and/or dual PPAR alpha/gamma agonists will be given. These new approaches might provide anti-hyperglycemic efficacy without the associated undesirable side-effects. However, further experimental and clinical studies evaluating the theoretical benefit and safety of this therapeutic strategy are needed. |
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