Fat-derived Factor Omentin Stimulates Endothelial Cell Function and Ischemia-induced Revascularization via Endothelial Nitric Oxide Synthase-dependent Mechanism
Fat-derived Factor Omentin Stimulates Endothelial Cell Function and Ischemia-induced Revascularization via Endothelial Nitric Oxide Synthase-dependent Mechanism
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DOI：
10.1074/jbc.m111.261818
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发表时间：
2012-01-02
影响因子：
4.8
通讯作者：
Ouchi, Noriyuki
中科院分区：
文献类型：
--
作者：
Maruyama, Sonomi;Shibata, Rei;Ouchi, Noriyuki
肥胖相关疾病与血管功能障碍和血运重建受损有关。网膜蛋白是一种脂肪源性分泌蛋白，其下调与肥胖并发症有关。在这里，我们研究了网膜蛋白是否在体外和体内调节内皮细胞功能和血运重建过程。表达网膜蛋白 (Ad-omentin) 的腺病毒载体的全身递送增强了野生型小鼠体内缺血肢体的血流恢复和毛细血管密度，同时伴随着 Akt 和内皮一氧化氮合酶 (eNOS) 磷酸化的增加。在培养的人脐静脉内皮细胞（HUVEC）中，生理浓度的重组网膜蛋白可增加其向血管样结构的分化，并在血清饥饿条件下降低细胞凋亡活性。网膜蛋白处理刺激了 HUVEC 中 Akt 和 eNOS 的磷酸化。通过显性失活 Akt 或 LY294002 治疗抑制 Akt 信号传导，可阻断大网膜素对 HUVEC 分化和存活的刺激作用，并逆转大网膜素刺激的 eNOS 磷酸化。 NOS 抑制剂预处理也减少了网膜素诱导的 HUVEC 分化和存活的增加。网膜蛋白还刺激 HUVEC 中 AMP 激活的蛋白激酶的磷酸化。显性失活 AMP 激活蛋白激酶的转导减少了网膜蛋白诱导的 Akt 磷酸化以及网膜蛋白刺激的 HUVEC 分化和存活的增加。重要的是，与野生型小鼠相比，全身施用 Ad-omentin 不会影响 eNOS 缺陷小鼠体内缺血肌肉的血流。这些数据表明，网膜蛋白通过其刺激 Akt-eNOS 信号通路的能力，促进内皮细胞功能和血运重建以应对缺血。
Obesity-related diseases are associated with vascular dysfunction and impaired revascularization. Omentin is a fat-derived secreted protein, which is down-regulated in association with obese complications. Here, we investigated whether omentin modulates endothelial cell function and revascularization processes in vitro and in vivo. Systemic delivery of an adenoviral vector expressing omentin (Ad-omentin) enhanced blood flow recovery and capillary density in ischemic limbs of wild-type mice in vivo, which were accompanied by increased phosphorylation of Akt and endothelial nitric oxide synthase (eNOS). In cultured human umbilical vein endothelial cells (HUVECs), a physiological concentration of recombinant omentin protein increased differentiation into vascular-like structures and decreased apoptotic activity under conditions of serum starvation. Treatment with omentin protein stimulated the phosphorylation of Akt and eNOS in HUVECs. Inhibition of Akt signaling by treatment with dominant-negative Akt or LY294002 blocked the stimulatory effects of omentin on differentiation and survival of HUVECs and reversed omentin-stimulated eNOS phosphorylation. Pretreatment with the NOS inhibitor also reduced the omentin-induced increase in HUVEC differentiation and survival. Omentin protein also stimulated the phosphorylation of AMP-activated protein kinase in HUVECs. Transduction with dominant-negative AMP-activated protein kinase diminished omentin-induced phosphorylation of Akt and omentin-stimulated increase in HUVEC differentiation and survival. Of importance, in contrast to wild-type mice, systemic administration of Ad-omentin did not affect blood flow in ischemic muscle in eNOS-deficient mice in vivo. These data indicate that omentin promotes endothelial cell function and revascularization in response to ischemia through its ability to stimulate an Akt-eNOS signaling pathway.