Cardiology and Cardiovascular Research, Institute of Physiology and University Hospital, Zürich, Switzerland Cardiology Unit, Department of Medicine, Karolinska University Hospital, Solna, 171 76 Stockholm, Sweden IRCCS Neuromed, Pozzilli, Italy.
Cardiology and Cardiovascular Research, Institute of Physiology and University Hospital, Zürich, Switzerland Cardiology Unit, Department of Medicine, Karolinska University Hospital, Solna, 171 76 Stockholm, Sweden.
Eur Heart J. 2015 Apr 1;36(13):817-28. doi: 10.1093/eurheartj/ehu179. Epub 2014 May 5.
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.
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-κB 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-kB 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 F2α and plasma levels of adhesion molecules.
Pin1 drives diabetic vascular disease by causing mitochondrial oxidative stress, eNOS dysregulation as well as NF-kB-induced inflammation. These findings provide molecular insights for novel mechanism-based therapeutic strategies in patients with diabetes.
糖尿病是心血管疾病的主要驱动因素，但潜在机制仍难以捉摸。脯氨酰异构酶 Pin1 识别特定的肽键，并调节改变细胞内平衡的蛋白质的功能。本研究调查了 Pin1 在糖尿病诱导的血管疾病中的作用。
在高葡萄糖暴露的人主动脉内皮细胞 (HAEC) 中，Pin1 上调诱导促氧化衔接蛋白 p66(Shc)的线粒体易位，随后细胞器破坏。在这种情况下，Pin1 识别内皮型一氧化氮合酶 (eNOS) 的抑制性磷酸化 Ser-116，导致 eNOS-窖蛋白-1 相互作用和减少 NO 可用性。Pin1 还介导高血糖诱导的 NF-κB p65核转位，触发 VCAM-1、ICAM-1 和 MCP-1 的表达。事实上，HAECs 中的 Pin1 基因沉默抑制了 p66(Shc)依赖性 ROS 产生，恢复了 NO 释放并减弱了 NF-kB p65 核转位。一致地，糖尿病 Pin1(-/-) 小鼠对线粒体氧化应激、内皮功能障碍和血管炎症具有保护作用。与年龄匹配的健康对照组相比，从糖尿病患者中分离的外周血单核细胞中也发现了 Pin1 的表达和活性增加。有趣的是，Pin1 的上调与血流介导的扩张受损、尿 8-异前列腺素 F2α 增加和血浆黏附分子水平升高有关。
Pin1 通过引起线粒体氧化应激、eNOS 失调以及 NF-kB 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提供了基于新机制的治疗策略的分子见解。
