Department of Internal Medicine, University of Torino, Torino, Italy.
Diabetes. 2010 Apr;59(4):1016-25. doi: 10.2337/db09-0858. Epub 2010 Jan 12.
Acylated ghrelin (AG) is a diabetogenic and orexigenic gastric polypeptide. These properties are not shared by the most abundant circulating form, which is unacylated (UAG). An altered UAG/AG profile together with an impairment of circulating endothelial progenitor cell (EPC) bioavailability were found in diabetes. Based on previous evidence for the beneficial cardiovascular effects of AG and UAG, we investigated their potential to revert diabetes-associated defects.
Healthy human subjects, individuals with type 2 diabetes, and ob/ob mice were AG or UAG infused. EPC mobilization in patients and mice was evaluated, and the underlying molecular mechanisms were investigated in bone marrow stromal cells. Recovered EPCs were also evaluated for the activity of senescence regulatory pathways and for NADPH oxidase activation by knocking down p47(phox) and Rac1. Finally, UAG modulation of human EPC vasculogenic potential was investigated in an in vivo mouse model.
Neither AG nor UAG had any effect in healthy subjects. However, systemic administration of UAG, but not AG, prevented diabetes-induced EPC damage by modulating the NADPH oxidase regulatory protein Rac1 and improved the vasculogenic potential both in individuals with type 2 diabetes and in ob/ob mice. In addition, unlike AG, UAG facilitated the recovery of bone marrow EPC mobilization. Crucial to EPC mobilization by UAG was the rescue of endothelial NO synthase (eNOS) phosphorylation by Akt, as UAG treatment was ineffective in eNOS knockout mice. Consistently, EPCs expressed specific UAG-binding sites, not recognized by AG.
These data provide the rationale for clinical applications of UAG in pathologic settings where AG fails.
酰化 ghrelin（AG）是一种致糖尿病和食欲刺激的胃多肽。这些特性与最丰富的循环形式，即未酰化（UAG），并不共享。在糖尿病中发现改变的 UAG/AG 谱与循环内皮祖细胞（EPC）生物利用度受损有关。基于先前关于 AG 和 UAG 的有益心血管作用的证据，我们研究了它们恢复与糖尿病相关缺陷的潜力。
健康的人体受试者、2 型糖尿病患者和 ob/ob 小鼠接受了 AG 或 UAG 输注。评估了患者和小鼠中的 EPC 动员情况，并在骨髓基质细胞中研究了潜在的分子机制。还评估了恢复的 EPC 对衰老调节途径的活性以及通过敲低 p47(phox)和 Rac1 对 NADPH 氧化酶激活的作用。最后，在体内小鼠模型中研究了 UAG 对人 EPC 血管生成潜能的调节作用。
AG 和 UAG 在健康受试者中均无任何作用。然而，全身性给予 UAG，但不是 AG，通过调节 NADPH 氧化酶调节蛋白 Rac1 来预防糖尿病引起的 EPC 损伤，并改善 2 型糖尿病患者和 ob/ob 小鼠的血管生成潜能。此外，与 AG 不同，UAG 促进了骨髓 EPC 的动员恢复。UAG 对 EPC 动员至关重要的是 Akt 对内皮型一氧化氮合酶（eNOS）磷酸化的挽救，因为 UAG 处理在 eNOS 敲除小鼠中无效。一致地，EPC 表达特定的 UAG 结合位点，而 AG 不能识别这些结合位点。
这些数据为 UAG 在 AG 失败的病理情况下的临床应用提供了依据。
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