Anti-Atherogenic Mechanisms of Drebrin

Drebrin 的抗动脉粥样硬化机制

• 批准号: 10532356
• 负责人: NEIL J. FREEDMAN
• 金额: $ 52.33万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-16 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10532356
• 关键词: Actin-Binding Protein; Angiotensin II; Antiatherogenic; Aorta; Apolipoprotein E; Arterial Fatty Streak; Arterial Injury; Arteries; Atherosclerosis; CX3CL1 gene; Carotid Arteries; Cd68; Cell Lineage; Cell Proliferation; Cells; Cholesterol; Common carotid artery; Congestive Heart Failure; Development; Disease; Down-Regulation; Dynamin; Endocytosis; Endocytosis Inhibition; Enzymes; Exhibits; Foam Cells; Fractalkine; GKLF protein; Generations; Genes; Glutathione Metabolism Pathway; Glutathione S-Transferase; Goals; Human; In Vitro; Inflammatory; Knock-in; Knowledge; LoxP-flanked allele; Macrophage; Mass Spectrum Analysis; Mediating; Medical; Memory; Microfilaments; Mission; Molecular; Morbidity - disease rate; Mus; Myocardial Infarction; NADPH Oxidase 1; Neurons; Nuclear; Nuclear Translocation; Phagocytes; Phenotype; Prevalence; Process; Production; Proteins; Public Health; Reactive Oxygen Species; Research; Role; Signal Transduction; Smooth Muscle Myocytes; Stroke; Testing; United States National Institutes of Health; Vascular Smooth Muscle; ascending aorta; atherogenesis; burden of illness; cell motility; congenic; cytokine; disability; drebrins; in vivo; mortality; novel therapeutic intervention; oxidized low density lipoprotein; response; transcription factor; transdifferentiation; vascular inflammation; vascular injury; western diet

We discovered that the actin-binding protein, Drebrin, is abundantly expressed in smooth muscle cells (SMCs) and is up-regulated in response to arterial injury in mice and to atherosclerosis in humans. Comparing WT with Dbn-/+ mice, we found that Drebrin inhibits SMC migration and proliferation, both in vitro and in vivo, through stabilization of actin filaments. In studies with SMC-specific Dbn-/- (SMC-Dbn-/-) mice, we found that SMC Drebrin limits angiotensin II-induced remodeling of the ascending aorta, in a manner that correlates with down-regulation of NADPH oxidase 1 (NOX1), decreased SMC reactive oxygen species (ROS) production and reduced vascular inflammation. Thus, Drebrin constrains not only the migratory/proliferative SMC phenotype but also the pro-inflammatory SMC phenotype evoked by vascular injury and angiotensin II. Congruently, we found that atherosclerosis is greater in SMC-Dbn-/-/Ldlr-/- than in congenic SMC-Dbn+/+/Ldlr-/- mice. Because SMC Drebrin negatively regulates atherosclerosis, our goals are to determine the mechanisms by which Drebrin regulates SMC pro-inflammatory signaling and whether enhanced SMC expression of Drebrin can inhibit atherogenesis. To this end, we performed SILAC/mass spectrometry studies on Dbn-/- and congenic WT SMCs. We found that whereas in Dbn-/- SMCs the ROS-defensive enzyme Glutathione-S-transferase µ1 (GSTM1) is down-regulated, the pro-inflammatory cytokine CX3CL1 (fractalkine) is up-regulated: thus we will investigate the role of these proteins in mediating the phenotype of Dbn-/- SMCs. Because endocytosis of NOX1 regulates ROS generation and activation of pro-inflammatory NFκB signaling and Drebrin has been shown to inhibit endocytosis, we will investigate whether Drebrin inhibits NOX1-mediated ROS generation by inhibiting endocytosis. A major focus of our studies will be pro-atherogenic SMC-derived foam cells, which SMC lineage tracing studies have shown, comprise ~40% of foam cells in atherosclerotic lesions. Our Preliminary Studies show that, compared with cognate Dbnflox/flox SMCs, Dbn-/- SMCs induced to transdifferentiate with cholesterol loading exhibited increased expression of the macrophage marker, CD68, and Kruppel-like factor 4 (KLF4), a transcription factor required for SMC-to-foam cell transdifferentiation. By grafting common carotid arteries from Dbnflox/flox and SMC-Dbn-/- mice into carotid arteries of congenic Apoe-/- mice, we also show that Drebrin deficiency augments transdifferentiation of SMCs to CD68+ cells in vivo. We will test the hypothesis that Drebrin inhibits atherogenesis by limiting SMC transdifferentiation into foam cells. To do so, we will establish whether Drebrin inhibits SMC-to-foam cell transdifferentiation and associated pro- inflammatory signaling, both in vitro and in vivo; determine if Drebrin inhibits SMC transdifferentiation through ROS-dependent mechanisms; and define the roles of GSTM1 and CX3CL1 in mediating Drebrin’s inhibitory effects on SMC transdifferentiation and pro-inflammatory signaling.

我们发现肌动蛋白结合蛋白Drebrin在平滑肌细胞（SMCs）中大量表达。

项目成果

Drebrin attenuates atherosclerosis by limiting smooth muscle cell transdifferentiation.

• DOI: 10.1093/cvr/cvab156
• 发表时间: 2021-04
• 期刊: Cardiovascular research
• 影响因子: 10.8
• 作者: Jiao‐Hui Wu;Lisheng Zhang;Igor Nepliouev;L. Brian;Taiqin Huang;Kamie P Snow;B. Schickling;E. Hauser;F. Miller;N. Freedman;Jonathan A Stiber