Endothelial Akt in Vascular Injury

蛋白激酶B/Akt是一种丝氨酸-苏氨酸激酶，其作用于磷脂酰肌醇3-激酶的下游 胰岛素样生长因子-1（insulin-like growth factor-1，IGF-1）、类固醇激素等内源性配体可诱导磷脂酰肌醇3激酶（PI 3 K）的表达 激素和他汀类药物Akt的磷酸化导致多种信号通路的调节， 潜在的心血管保护作用，包括糖原合成酶激酶（GSK）-3b的失活， 葡萄糖转运蛋白（Glut）-4的活化和半胱天冬酶-9的抑制。然而，内皮细胞Akt在 血管损伤和动脉粥样硬化是未知的。在内皮细胞中，最近的研究集中在 Akt激活内皮型一氧化氮合酶（eNOS）。内皮NOS是Akt的底物， 在Ser 1179处磷酸化eNOS，导致eNOS活性和NO产生增加。内皮素- 衍生的NO由于其血管舒张、抗炎和抗氧化而具有心血管保护作用 特性.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。 虽然Akt可能在血管内稳态中发挥关键作用，但目前所知不多 关于内皮细胞Akt在血管疾病中的作用。这种限制主要是由于缺乏 药理学工具可用于Akt的组织特异性调节。因此， 使用组织限制性靶向基因破坏或调节更有可能阐明特异性功能 Akt在内皮细胞中的表达。为了这个目的，我们已经开发了转基因小鼠， Akt的组成型活性或显性失活突变体，其可以诱导靶向于 使用Cre/loxP系统对内皮细胞进行了检测。提出了三个具体目标，将研究 在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.