Ackah Eric, Yu Jun, Zoellner Stefan, Iwakiri Yasuko, Skurk Carsten, Shibata Rei, Ouchi Noriyuki, Easton Rachael M, Galasso Gennaro, Birnbaum Morris J, Walsh Kenneth, Sessa William C
Department of Pharmacology and Program in Vascular Cell Signaling and Therapeutics, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut 06536-0812, USA.
J Clin Invest. 2005 Aug;115(8):2119-27. doi: 10.1172/JCI24726.
Akt, or protein kinase B, is a multifunctional serine-threonine protein kinase implicated in a diverse range of cellular functions including cell metabolism, survival, migration, and gene expression. However, the in vivo roles and effectors of individual Akt isoforms in signaling are not explicitly clear. Here we show that the genetic loss of Akt1, but not Akt2, in mice results in defective ischemia and VEGF-induced angiogenesis as well as severe peripheral vascular disease. Akt1 knockout (Akt1-/-) mice also have reduced endothelial progenitor cell (EPC) mobilization in response to ischemia, and reintroduction of WT EPCs, but not EPCs isolated from Akt1-/- mice, into WT mice improves limb blood flow after ischemia. Mechanistically, the loss of Akt1 reduces the basal phosphorylation of several Akt substrates, the migration of fibroblasts and ECs, and NO release. Reconstitution of Akt1-/- ECs with Akt1 rescues the defects in substrate phosphorylation, cell migration, and NO release. Thus, the Akt1 isoform exerts an essential role in blood flow control, cellular migration, and NO synthesis during postnatal angiogenesis.
Akt，即蛋白激酶B，是一种多功能丝氨酸 - 苏氨酸蛋白激酶，涉及多种细胞功能，包括细胞代谢、存活、迁移和基因表达。然而，单个Akt亚型在信号传导中的体内作用和效应器尚不完全清楚。在这里，我们表明，小鼠中Akt1而非Akt2的基因缺失会导致缺血和VEGF诱导的血管生成缺陷以及严重的外周血管疾病。Akt1基因敲除（Akt1-/-）小鼠对缺血的反应中内皮祖细胞（EPC）动员也减少，将野生型EPC而非从Akt1-/-小鼠分离的EPC重新引入野生型小鼠可改善缺血后的肢体血流。从机制上讲，Akt1的缺失会降低几种Akt底物的基础磷酸化、成纤维细胞和内皮细胞的迁移以及一氧化氮的释放。用Akt1重建Akt1-/-内皮细胞可挽救底物磷酸化、细胞迁移和一氧化氮释放方面的缺陷。因此，Akt1亚型在出生后血管生成过程中的血流控制、细胞迁移和一氧化氮合成中发挥着重要作用。
