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.



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.