Duan Sheng Zhong, Usher Michael G, Mortensen Richard M
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109-0622, USA.
Circ Res. 2008 Feb 15;102(3):283-94. doi: 10.1161/CIRCRESAHA.107.164384.
Peroxisome proliferator-activated receptor (PPAR)-gamma is a nuclear receptor and transcription factor in the steroid superfamily. PPAR-gamma agonists, the thiazolidinediones, are clinically used to treat type 2 diabetes. In addition to its function in adipogenesis and increasing insulin sensitivity, PPAR-gamma also plays critical roles in the vasculature. In vascular endothelial cells, PPAR-gamma activation inhibits endothelial inflammation by suppressing inflammatory gene expression and therefore improves endothelial dysfunction. In vascular smooth muscle cells, PPAR-gamma activation inhibits proliferation and migration and promotes apoptosis. In macrophages, PPAR-gamma activation suppresses inflammation by regulating gene expression and increases cholesterol uptake and efflux. A recurring theme in many cell types is the modulation of the innate immunity system particularly through altering the activity of the nuclear factor kappaB. This system is likely to be even more prominent in modulating disease in vascular cells. The effects of PPAR-gamma in the vascular cells translate into the beneficial function of this transcription factor in vascular disorders, including hypertension and atherosclerosis. Both human genetic studies and animal studies using transgenic mice have demonstrated the importance of PPAR-gamma in these disorders. However, recent clinical studies have raised significant concerns about the cardiovascular side effects of thiazolidinediones, particularly rosiglitazone. Weighing the potential benefit and harm of PPAR-gamma activation and exploring the functional mechanisms may provide a balanced view on the clinical use of these compounds and new approaches to the future therapeutics of vascular disorders associated with diabetes.
过氧化物酶体增殖物激活受体（PPAR）-γ是类固醇超家族中的一种核受体和转录因子。PPAR-γ激动剂噻唑烷二酮类药物在临床上用于治疗2型糖尿病。除了在脂肪生成和提高胰岛素敏感性方面的作用外，PPAR-γ在血管系统中也起着关键作用。在血管内皮细胞中，PPAR-γ激活通过抑制炎症基因表达来抑制内皮炎症，从而改善内皮功能障碍。在血管平滑肌细胞中，PPAR-γ激活抑制增殖和迁移并促进凋亡。在巨噬细胞中，PPAR-γ激活通过调节基因表达来抑制炎症，并增加胆固醇摄取和流出。在许多细胞类型中反复出现的一个主题是对先天免疫系统的调节，特别是通过改变核因子κB的活性。该系统在调节血管细胞疾病方面可能更为突出。PPAR-γ在血管细胞中的作用转化为该转录因子在包括高血压和动脉粥样硬化在内的血管疾病中的有益功能。人类遗传学研究和使用转基因小鼠的动物研究均已证明PPAR-γ在这些疾病中的重要性。然而，最近的临床研究对噻唑烷二酮类药物，尤其是罗格列酮的心血管副作用提出了重大担忧。权衡PPAR-γ激活的潜在益处和危害并探索其功能机制，可能会为这些化合物的临床应用以及糖尿病相关血管疾病未来治疗的新方法提供一个平衡的观点。
