Endothelial Akt in Vascular Injury

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DESCRIPTION (provided by applicant): 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.