Endothelial Akt in Vascular Injury

蛋白激酶B/Akt是一种丝氨酸-苏氨酸激酶，作用于磷脂酰肌醇3-激酶的下游 (PI3K)，由胰岛素、胰岛素样生长因子-1、类固醇等多种内源性配体诱导。 荷尔蒙和他汀类药物。Akt的磷酸化导致多种信号通路的调制 潜在的心血管保护作用包括糖原合成酶激酶(GSK)-3b的失活， 激活葡萄糖转运体(GLUT)-4，抑制caspase-9。然而，内皮细胞Akt在其中的作用 血管损伤和动脉粥样硬化尚不清楚。在内皮细胞方面，最近的研究集中在 Akt激活内皮型一氧化氮合酶(ENOS)内皮一氧化氮合酶是Akt的底物，它 使eNOS在Ser 1179处磷酸化，导致eNOS活性增加和NO产生。内皮- 由于其血管扩张、抗炎和抗氧化作用，衍生的一氧化氮具有心血管保护作用。 属性。因此，通过Akt刺激内皮细胞中的eNOS可能是一个有希望的靶点 减轻动脉粥样硬化和血管炎症。 尽管Akt可能在血管内稳态中发挥关键作用，但人们对此知之甚少。 血管内皮细胞Akt在血管疾病中的作用。这一限制主要是由于缺乏 可用于组织特异性调节Ak.的药理学工具。因此，一种遗传方法 使用组织限制性靶向基因破坏或调节更有可能阐明特定的功能 血管内皮细胞中Akt的含量。为此，我们培育了过度表达的转基因小鼠。 Akt的构成活性或显性负性突变体，可诱导靶向 使用Cre/loxP系统的内皮细胞。提出了三个具体目标，这将研究 血管损伤和动脉粥样硬化模型中的内皮Akt。

Protein kinase B/Akt is a serine-threonine kinase which acts downstream of phosphatidylinositol 3-kinase (PI3K) and is induced by many endogenous ligands such as insulin, insulin-like growth factor-1, steroid hormones, and statins. Phosphorylation of Akt leads to modulation of a variety of signal pathways with potential cardiovascular protective effects including inactivation of glycogen synthase kinase (GSK)-3b, activation of glucose transporter (Glut)-4, and inhibition of caspase-9. However, the role of endothelial Akt in vasculary injury and atherosclerosis is not known. In endothelial cells, recent studies have focused on the activation of endothelial nitric oxide synthase (eNOS) by Akt. Endothelial NOS is a substrate for Akt, which phosphorylates eNOS at Ser 1179, leading to increased eNOS activity and NO production. Endothelium- derived NO is cardiovascularly protective due to its vasodilating, anti-inflammatory, and antioxidative properties. Stimulation of eNOS via Akt in endothelial cells, therefore, may be a promising target for attenuating atherosclerosis and vascular inflammation. Although Akt could potentially play a critical role in vascular homeostasis, not much is known regarding the contribution of endothelial Akt in vascular disease. This limitation is mostly due to the lack of pharmacological tools available for a tissue-specific modulation of Akt.Consequently, a genetic approach using tissue-restricted targeted gene disruption or modulation is more likely to elucidate the specific function of Akt in the endothelium. For this purpose, we have developed transgenic mice overexpressing constitutively-active or dominant-negative mutants of Akt, which could be inducibly targeted to the endothelium using the Cre/loxP system. Three specific aims are proposed, which will study the role of endothelial Akt in models of vascular injury and atherosclerosis.