Mechanism of atheroprotective function of Akt3 kinase

Akt3激酶的动脉粥样硬化保护功能机制

• 批准号: 9414577
• 负责人: EUGENE A PODREZ
• 金额: $ 39.63万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-09 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9414577
• 关键词: AKT3 gene; Ablation; Apolipoprotein E; Apoptosis; Arteries; Atherosclerosis; Bone Marrow; Cardiovascular Diseases; Cardiovascular system; Cell Line; Cell physiology; Cells; Chimera organism; Cholesterol; Cholesterol Esters; Cholesterol Homeostasis; Coronary Arteriosclerosis; Disease; Esterification; Event; Family; Foam Cells; Genes; Genetic; Goals; Human; In Vitro; Lipids; Lipoproteins; Mammals; Marrow; Molecular; Mus; Oxides; Pathway interactions; Patients; Phenotype; Phospholipids; Phosphorylation; Phosphotransferases; Physiology; Pinocytosis; Protein Isoforms; Protein Kinase; Protein-Serine-Threonine Kinases; Proteins; Regulation; Role; Signal Pathway; Specificity; Sterol O-Acyltransferase; Testing; atherogenesis; atheroprotective; cell growth; glucose metabolism; in vivo; knock-down; lipid metabolism; macrophage; monocyte; mutant; novel; novel strategies; novel therapeutic intervention; prevent; public health relevance; sterol O-acyltransferase 1; uptake

 DESCRIPTION (provided by applicant): Serine/threonine kinases Akt (also known as PKB), are among the most important and versatile protein kinases at the core of human physiology and disease. Akt regulate numerous cellular processes, including cell growth, glucose and lipid metabolism, differentiation, proliferation, and apoptosis. Three highly homologous Akt isoforms, encoded by three separate genes, are expressed in mammals. Combined deletions of the three Akt isoforms in the mouse suggest compensatory and complementary roles of isoforms. However, the three isoforms also have distinct functions, even though the mechanisms of specificity are only starting to emerge. Studies of the role of Akt, and specifically of Akt isofors, in atherogenesis are very limited. It has been recently shown that genetic ablation of Akt1 promotes coronary atherosclerosis via the enhanced expression of proinflammatory genes in the artery wall in a macrophage independent manner. We have recently explored the role of Akt3 in atherosclerosis using mice with a genetic ablation of the Akt3 gene. Our studies have demonstrated a specific, macrophage dependent, atheroprotective role for Akt3 in hyperlipidemic ApoE-/- mice. In a step-by-step fashion, we tested various potential mechanisms and demonstrated that the absence of Akt3 transforms macrophage into cell which aggressively accumulates cholesterol esters via two mechanisms: increased lipoprotein uptake via pinocytosis, and parallel increased protein stability of cholesterol esterifying enzyme ACAT1 (also known as SOAT1). Multiple lines of evidence suggested that Akt3 suppresses atherosclerosis by restricting cholesteryl ester accumulation and foam cell formation in macrophages, an early and critical step in atherogenesis. The mechanism is Akt isoform specific, and our preliminary studies suggest that one mechanism for specificity is via differentia subcellular localization of Akt1 (a major isoform in macrophages) and Akt3 in macrophages. The long-term goal of this proposal is to investigate the molecular mechanism of Akt3 regulation of macrophage function. As a specific hypothesis, we propose that Akt3 specifically suppresses transformation of macrophage into lipid accumulating phenotype by inhibiting macrophage pinocytosis and by regulating a particular branch of cholesterol metabolism - cholesterol esterification via direct regulation of ACAT1 protein stability. We will investigate the role of AK3 in atherogenesis in vivo and in vitro with a particular focus on the molecular mechanisms of regulation of Akt3 activity, ACAT1 expression and pinocytosis.

 描述(申请人提供)：丝氨酸/苏氨酸激酶Akt(也称为PKB)，是在人类生理和疾病的核心中最重要和最通用的蛋白激酶之一。AKT调节多种细胞过程，包括细胞生长、糖脂代谢、分化、增殖和凋亡。三种高度同源的Akt亚型由三个独立的基因编码，在哺乳动物中表达。小鼠体内三种Akt亚型的联合缺失暗示了亚型的代偿和互补作用。然而，这三种异构体也有不同的功能，尽管特异性的机制才刚刚开始出现。对Akt，特别是Akt异构体在动脉粥样硬化形成中的作用的研究非常有限。最近的研究表明，Akt1的基因消融通过非依赖巨噬细胞的方式促进动脉壁促炎症基因的表达，从而促进冠状动脉粥样硬化。我们最近利用基因去除AKT3基因的小鼠探索了AKT3在动脉粥样硬化中的作用。我们的研究已经证明了AKT3对高脂血症ApoE-/-小鼠具有特异性的、巨噬细胞依赖的动脉粥样硬化保护作用。我们以循序渐进的方式测试了各种可能的机制，并证明了AKT3的缺失通过两种机制将巨噬细胞转化为积极积累胆固醇酯的细胞：通过吞噬作用增加脂蛋白摄取，以及同时增加胆固醇酯化酶ACAT1(也称为SOAT1)的蛋白质稳定性。多条证据表明，AKT3通过限制巨噬细胞中胆固醇酯的积累和泡沫细胞的形成来抑制动脉粥样硬化，这是动脉粥样硬化形成的早期和关键步骤。这种机制是Akt亚型特异性的，我们的初步研究表明，这种特异性的机制之一是通过Akt1(巨噬细胞中的主要亚型)和AKT3在巨噬细胞中的不同亚细胞定位。这项建议的长期目标是研究AKT3调节巨噬细胞功能的分子机制。作为一种特定的假设，我们认为AKT3通过抑制巨噬细胞吞噬作用和通过直接调节ACAT1蛋白稳定性来调节胆固醇代谢的一个特定分支--胆固醇酯化，从而特异性地抑制巨噬细胞向脂质积聚表型的转化。我们将研究AK3在体内和体外动脉粥样硬化形成中的作用，重点是调节AKT3活性、ACAT1表达和胞饮作用的分子机制。

项目成果

Enhanced Akt3 kinase activity reduces atherosclerosis in hyperlipidemic mice in a gender-dependent manner.

• DOI: 10.1016/j.jbc.2023.105425
• 发表时间: 2023-12
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Zhang, Lifang;Altemus, Jessica;Ding, Liang;Cherepanova, Olga;Byzova, Tatiana, V;Podrez, Eugene A.
• 通讯作者: Podrez, Eugene A.