Nicotinamide phosphoribosyltransferase imparts human endothelial cells with extended replicative lifespan and enhanced angiogenic capacity in a high glucose environment
Nicotinamide phosphoribosyltransferase imparts human endothelial cells with extended replicative lifespan and enhanced angiogenic capacity in a high glucose environment
复制标题
DOI：
10.1111/j.1474-9726.2009.00453.x
复制
发表时间：
2009-04-01
期刊：
影响因子：
7.8
通讯作者：
Pickering, J. Geoffrey
中科院分区：
文献类型：
--
作者：
Borradaile, Nica M.;Pickering, J. Geoffrey
内皮功能障碍是衰老相关血管疾病的一个特征，在糖尿病期间会恶化。高葡萄糖可以通过细胞活性氧的积累损害内皮细胞（EC）的功能，这种损害也可以限制复制寿命。烟酰胺磷酸核糖基转移酶（Nampt），也被称为PBEF和visfatin，是烟酰胺NAD（+）回收的限速酶，并通过SIRT1赋予抗氧化应激能力。因此，我们试图确定Nampt表达是否能够抵抗高糖的有害影响，并在这种病理环境中赋予人类血管EC生存优势。用编码eGFP或eGFP- nampt的逆转录病毒感染人主动脉EC，并通过facs筛选获得具有相似、适度转基因表达的群体。使用慢性葡萄糖暴露模型，我们追踪了EC种群的衰老，评估了细胞代谢，并确定了体外血管生成功能。过表达Nampt增加增殖和延长复制寿命，并且在葡萄糖过载时优先这样做。通过适度增加有氧糖酵解，Nampt的表达延迟了衰老标记物和限制活性氧在高葡萄糖中的积累。此外，nanpt过表达的EC形成的管网更广泛和葡萄糖抵抗，这与sirt1介导的抗血管生成转录因子fox01的抑制一致。我们得出结论，Nampt使增殖的人类EC能够抵抗衰老和高葡萄糖的氧化应激，并有效地利用多余的葡萄糖来支持复制寿命和血管生成活性。因此，在衰老和高血糖期间，如动脉粥样硬化和糖尿病相关血管疾病，内皮细胞Nampt活性的增强可能对需要基于ec的血管修复和再生的情况有益。
Endothelial dysfunction is a characteristic of aging-related vascular disease and is worsened during diabetes. High glucose can impair endothelial cell (EC) function through cellular accumulation of reactive oxygen species, an insult that can also limit replicative lifespan. Nicotinamide phosphoribosyltransferase (Nampt), also known as PBEF and visfatin, is rate-limiting for NAD(+) salvage from nicotinamide and confers resistance to oxidative stress via SIRT1. We therefore sought to determine if Nampt expression could resist the detrimental effects of high glucose and confer a survival advantage to human vascular EC in this pathologic environment. Human aortic EC were infected with retrovirus encoding eGFP or eGFP-Nampt, and FACS-selected to yield populations with similar, modest transgene expression. Using a chronic glucose exposure model we tracked EC populations to senescence, assessed cellular metabolism, and determined in vitro angiogenic function. Overexpression of Nampt increased proliferation and extended replicative lifespan, and did so preferentially during glucose overload. Nampt expression delayed markers of senescence and limited reactive oxygen species accumulation in high glucose through a modest increase in aerobic glycolysis. Furthermore, tube networks formed by Nampt-overexpressing EC were more extensive and glucose-resistant, in accordance with SIRT1-mediated repression of the anti-angiogenic transcription factor, FoxO1. We conclude that Nampt enables proliferating human EC to resist the oxidative stress of aging and of high glucose, and to productively use excess glucose to support replicative longevity and angiogenic activity. Enhancing endothelial Nampt activity may thus be beneficial in scenarios requiring EC-based vascular repair and regeneration during aging and hyperglycemia, such as atherosclerosis and diabetes-related vascular disease.