Division of Cardiology, Department of Medicine, Helsinki University Central Hospital and Biomedicum, Haartmaninkatu 8, 00029 Helsinki, Finland.
Nat Rev Endocrinol. 2010 Aug;6(8):454-63. doi: 10.1038/nrendo.2010.89. Epub 2010 Jun 22.
The global pandemic of diabetes mellitus portends an alarming rise in the prevalence of microvascular complications, despite advanced therapies for hyperglycemia, hypertension and dyslipidemia. Peroxisome proliferator-activated receptor alpha (PPARalpha) is expressed in organs affected by diabetic microvascular disease (retina, kidney and nerves), and its expression is regulated specifically in these tissues. Experimental evidence suggests that PPARalpha activation attenuates or inhibits several mediators of vascular damage, including lipotoxicity, inflammation, reactive oxygen species generation, endothelial dysfunction, angiogenesis and thrombosis, and thus might influence intracellular signaling pathways that lead to microvascular complications. PPARalpha has emerged as a novel target to prevent microvascular disease, via both its lipid-related and lipid-unrelated actions. Despite strong experimental evidence of the potential benefits of PPARalpha agonists in the prevention of vascular damage, the evidence from clinical studies in patients with diabetes mellitus remains limited. Promising findings from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study on microvascular outcomes are countered by elevations in participants' homocysteine and creatinine levels that might potentially attenuate the benefits of PPARalpha activation. This Review focuses on the role of PPARalpha activation in diabetic microvascular disease and highlights the available experimental and clinical evidence from studies of PPARalpha agonists.
尽管针对高血糖、高血压和血脂异常已有先进的治疗方法，但糖尿病性微血管并发症的患病率仍呈全球流行趋势，令人警惕。过氧化物酶体增殖物激活受体 α（PPARα）在受糖尿病性微血管疾病影响的器官（视网膜、肾脏和神经）中表达，并在这些组织中特异性调节其表达。实验证据表明，PPARα 激活可减轻或抑制几种血管损伤介质，包括脂毒性、炎症、活性氧生成、内皮功能障碍、血管生成和血栓形成，因此可能影响导致微血管并发症的细胞内信号通路。PPARα 通过其与脂质相关和与脂质无关的作用，已成为预防微血管疾病的新靶点。尽管有强有力的实验证据表明 PPARα 激动剂在预防血管损伤方面具有潜在益处，但糖尿病患者的临床研究证据仍然有限。Fenofibrate Intervention and Event Lowering in Diabetes（FIELD）研究中关于微血管结局的有希望的发现，被参与者同型半胱氨酸和肌酐水平升高所抵消，这些水平升高可能会削弱 PPARα 激活的益处。这篇综述重点介绍了 PPARα 激活在糖尿病性微血管疾病中的作用，并强调了来自 PPARα 激动剂研究的现有实验和临床证据。
