Targeting prolyl-isomerase Pin1 prevents mitochondrial oxidative stress and vascular dysfunction: insights in patients with diabetes
Targeting prolyl-isomerase Pin1 prevents mitochondrial oxidative stress and vascular dysfunction: insights in patients with diabetes
复制标题
DOI：
10.1093/eurheartj/ehu179
复制
发表时间：
2015-04-01
影响因子：
39.3
通讯作者：
Cosentino, Francesco
中科院分区：
文献类型：
--
作者：
Paneni, Francesco;Costantino, Sarah;Cosentino, Francesco
目标 糖尿病是心血管疾病的主要驱动因素，但其潜在机制仍然难以捉摸。脯氨酰异构酶 Pin1 识别特定肽键并调节改变细胞稳态的蛋白质功能。本研究调查了 Pin1 在糖尿病诱发的血管疾病中的作用。方法和结果在暴露于高葡萄糖的人主动脉内皮细胞 (HAEC) 中，Pin1 诱导的促氧化接头 p66 (Shc) 线粒体易位上调，并随后导致细胞器破坏。在这种情况下，Pin1 识别内皮一氧化氮合酶 (eNOS) 的 Ser-116 抑制性磷酸化，导致 eNOS-caveolin-1 相互作用并降低 NO 可用性。 Pin1 还介导高血糖诱导的 NF-kappa B p65 核转位，触发 VCAM-1、ICAM-1 和 MCP-1 表达。事实上，HAEC 中 Pin1 的基因沉默抑制了 p66(Shc) 依赖性 ROS 的产生，恢复了 NO 的释放并削弱了 NF-kappa B p65 核转位。一致地，糖尿病 Pin1(-/-) 小鼠受到保护，免受线粒体氧化应激、内皮功能障碍和血管炎症的影响。与年龄匹配的健康对照相比，从糖尿病患者分离的外周血单核细胞中也发现 Pin1 的表达和活性增加。有趣的是，Pin1 上调与血流介导的扩张受损、尿液 8-异前列腺素 F-2 α 和粘附分子血浆水平增加有关。 结论 Pin1 通过引起线粒体氧化应激、eNOS 失调以及 NF-kappa B 诱导的炎症来驱动糖尿病血管疾病。这些发现为糖尿病患者基于机制的新型治疗策略提供了分子见解。
Aim Diabetes is a major driver of cardiovascular disease, but the underlying mechanisms remain elusive. Prolyl-isomerase Pin1 recognizes specific peptide bonds and modulates function of proteins altering cellular homoeostasis. The present study investigates Pin1 role in diabetes-induced vascular disease.Methods and results In human aortic endothelial cells (HAECs) exposed to high glucose, up-regulation of Pin1-induced mitochondrial translocation of pro-oxidant adaptor p66(Shc) and subsequent organelle disruption. In this setting, Pin1 recognizes Ser-116 inhibitory phosphorylation of endothelial nitric oxide synthase (eNOS) leading to eNOS-caveolin-1 interaction and reduced NO availability. Pin1 also mediates hyperglycaemia-induced nuclear translocation of NF-kappa B p65, triggering VCAM-1, ICAM-1, and MCP-1 expression. Indeed, gene silencing of Pin1 in HAECs suppressed p66(Shc)-dependent ROS production, restored NO release and blunted NF-kappa B p65 nuclear translocation. Consistently, diabetic Pin1(-/-) mice were protected against mitochondrial oxidative stress, endothelial dysfunction, and vascular inflammation. Increased expression and activity of Pin1 were also found in peripheral blood monocytes isolated from diabetic patients when compared with age-matched healthy controls. Interestingly, enough, Pin1 up-regulation was associated with impaired flow-mediated dilation, increased urinary 8-iso-prostaglandin F-2 alpha and plasma levels of adhesion molecules.Conclusions Pin1 drives diabetic vascular disease by causing mitochondrial oxidative stress, eNOS dysregulation as well as NF-kappa B-induced inflammation. These findings provide molecular insights for novel mechanism-based therapeutic strategies in patients with diabetes.