Reduced expression of endothelial nitric oxide synthase (eNOS) is a hallmark of endothelial dysfunction in diabetes, which predisposes diabetic patients to numerous cardiovascular complications including blunted angiogenesis. The Krüppel-like factor (KLF) five has been implicated as a central regulator of cardiovascular remodeling, but its role in endothelial cells (ECs) remains poorly understood. We show here that expression of endothelial KLF5 was significantly increased in the ECs from mouse diabetes mellitus type 2 (T2DM) model, when compared to non-diabetic or T1DM mouse. KLF5 up-regulation by insulin was dependent on activation of multiple pathways, including mammalian target of rapamycin, oxidative stress and Protein kinase C pathways. Hyperinsulinemia-induced KLF5 inhibited endothelial function and migration, and thereby compromised in vitro and in vivo angiogenesis. Mechanistically, KLF5 acted in concert with the MTA1 coregulator to negatively regulate NOS3 transcription, thereby leading to the diminished eNOS levels in ECs. Conversely, potentiation of cGMP content (the essential downstream effector of eNOS signaling) by pharmacological approaches successfully rescued the endothelial proliferation and in vitro tube formation, in the HUVECs overexpressing the exogenous KLF5. Collectively, the available data suggest that the augmentation of endothelial KLF5 expression by hyperinsulinemia may represent a novel mechanism for negatively regulating eNOS expression, and may thus help to explain for the T2DM-related endothelial dysfunction at the transcriptional level.

中文翻译：

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高胰岛素血症诱导的KLF5介导糖尿病内皮细胞中的内皮血管生成功能障碍。

内皮型一氧化氮合酶（eNOS）的表达降低是糖尿病中内皮功能障碍的标志，这使糖尿病患者易患多种心血管并发症，包括血管新生。Krüppel样因子（KLF）5被认为是心血管重塑的中央调节剂，但其在内皮细胞（EC）中的作用仍知之甚少。我们在这里显示，与非糖尿病或T1DM小鼠相比，来自小鼠2型糖尿病（T2DM）模型的EC中内皮KLF5的表达显着增加。胰岛素对KLF5的上调取决于多种途径的激活，包括哺乳动物雷帕霉素靶标，氧化应激和蛋白激酶C途径。高胰岛素血症诱导的KLF5抑制内皮功能和迁移，从而损害了体外和体内血管生成。从机理上讲，KLF5与MTA1调节器协同作用，对负调节NOS3转录，从而导致EC中的eNOS水平降低。相反，在过度表达外源性KLF5的HUVEC中，通过药理学方法增强cGMP含量（eNOS信号的重要下游效应物）可成功拯救内皮细胞增殖和体外管形成。总的来说，现有数据表明高胰岛素血症可增加内皮KLF5的表达，可能代表一种负调控eNOS表达的新机制，因此可能有助于在转录水平上解释T2DM相关的内皮功能障碍。