miRNA-mediated reduction of VSMC foam cell formation

miRNA 介导的 VSMC 泡沫细胞形成减少

• 批准号: 10376766
• 负责人: MICHAEL V AUTIERI
• 金额: $ 53.57万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-23 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10376766
• 关键词: Adaptor Signaling Protein; Anti-Inflammatory Agents; Antiinflammatory Effect; Apoptosis; Arterial Fatty Streak; Arteries; Atherosclerosis; Attenuated; Blood Vessels; Carotid Arteries; Cell Cycle; Cells; Cholesterol; Data; Development; Disease; Down-Regulation; Event; Foam Cells; Functional disorder; Funding; Goals; Homeostasis; Hyperlipidemia; Immunohistochemistry; Inflammatory; Knockout Mice; Ligation; Link; Lipids; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Medial; Mediating; MicroRNAs; Modeling; Molecular; Mus; Muscle; Mutation; Pathway interactions; Patients; Pharmacotherapy; Phenotype; Process; Publishing; Regulation; Reporting; Role; Small Interfering RNA; Smooth Muscle Myocytes; Stimulus; Syndrome; Testing; Therapeutic; Vascular Diseases; Vascular Proliferation; Vascular Smooth Muscle; Work; atherogenesis; atheroprotective; cell injury; cell type; conditional knockout; cytokine; hypercholesterolemia; in vivo; interleukin-19; macrophage; novel; oxidized low density lipoprotein; protein protein interaction; receptor; response; restenosis; transdifferentiation; uptake; vascular smooth muscle cell proliferation

The transformation of vascular smooth muscle cells (VSMC) into foam cells leading to increased plaque size and decreased stability is a key, yet understudied step in atherogenesis. Our work in the previous funding cycle (HL117724) demonstrated that Interleukin-19 (IL-19), a novel, anti-inflammatory cytokine, attenuates atherosclerosis by multiple anti-inflammatory effects on VSMC as well as by increasing lipid uptake and efflux in macrophage. In published and preliminary studies described here, we show that IL-19 reduces lipid accumulation in VSMC, an atheroprotective event, but without modifying expression of lipid receptors or transporters. IL-19 induces expression of miR133a, a muscle-specific miRNA previously ascribed to regulate VSMC phenotype. Although unrecognized and unreported, we have identified that miR133a can target and reduce expression of Low Density Lipoprotein Receptor Adaptor Protein 1, (LDLRAP1), an adaptor protein which functions to internalize the LDL receptor. Patients with mutations in LDLRAP1 have LDL receptor malfunction leading to hyperlipidemia and Autosomal Recessive Hypercholesterolemia (ARH) disorder. Nothing at all is known about a role for miR133a in regulation of lipid uptake and development of atherosclerosis. Similarly, nothing at all has been published about LDLRAP1 expression, function, and participation in VSMC foam cell formation. We have reported that that both miR133a and LDLRAP1 regulate oxLDL uptake in VSMC. LDLRAP1 is induced in VSMC by oxLDL, is not detectible in normal medial VSMC, but is expressed in plaque and neointimal VSMC of injured arteries. IL-19 can reduce LDLRAP1 expression and oxLDL uptake in VSMC. Both miR133a and LDLRAP1regulate VSMC proliferation, previously unrecognized functions for these molecules. Preliminary studies indicate that the LDLRAP1+/- mouse has increased atherosclerosis, but reduced restenosis. In this competitive renewal application, we hypothesize that LDLRAP1 can be selectively reduced in VSMC because miR133a is muscle specific, and that reduction of lipid uptake by VSMC is atheroprotective and could also attenuate vascular proliferative syndromes. The overall goals of this application are to determine causative roles for miR133a and LDLRAP1 in VSMC lipid uptake, proliferation, atherogenesis, cholesterol-induced phenotype modulation, and vascular restenosis.

血管平滑肌细胞（VSMC）转化为泡沫细胞，导致斑块增加 尺寸和稳定性降低是动脉粥样硬化形成中的关键但未充分研究的步骤。我们在过去的工作 资助周期（HL 117724）证明白细胞介素-19（IL-19），一种新的抗炎细胞因子， 通过对VSMC的多种抗炎作用以及通过增加脂质 在巨噬细胞中的摄取和流出。在这里描述的已发表和初步研究中，我们表明IL-19 减少VSMC中的脂质积聚，这是一种动脉粥样硬化保护事件，但不改变脂质的表达 受体或转运蛋白。IL-19诱导miR 133 a的表达，miR 133 a是一种肌肉特异性miRNA， 调节VSMC表型。虽然没有得到承认和报告，我们已经确定， miR 133 a可以靶向并降低低密度脂蛋白受体衔接蛋白1的表达， （LDLRAP 1），一种衔接蛋白，其功能是内化LDL受体。突变的患者 LDLRAP 1具有LDL受体功能障碍，导致高脂血症和常染色体隐性遗传 高胆固醇血症（ARH）病症。目前还不清楚miR 133 a在调节细胞凋亡中的作用。 脂质摄取和动脉粥样硬化的发展。同样，也没有任何关于 LDLRAP 1表达、功能和参与VSMC泡沫细胞形成。我们报道说， miR 133 a和LDLRAP 1均调节VSMC中oxLDL摄取。LDL RAP 1在VSMC中被oxLDL诱导， 在正常中膜VSMC中检测不到，但在损伤动脉的斑块和新生内膜VSMC中表达。 IL-19可降低VSMC中LDLRAP 1的表达和oxLDL的摄取。miR 133 a和LDLRAP 1均调节 VSMC增殖，以前未认识到这些分子的功能。初步研究表明 LDLRAP 1 +/-小鼠动脉粥样硬化增加，但再狭窄减少。在这个竞争激烈的 更新申请，我们假设LDLRAP 1可以在VSMC中选择性降低，因为miR 133 a 是肌肉特异性，VSMC摄取脂质的减少具有动脉粥样硬化保护作用， 血管增生综合征本应用程序的总体目标是确定 miR 133 a和LDLRAP 1在VSMC脂质摄取、增殖、动脉粥样硬化形成、胆固醇诱导表型中的作用 调制和血管再狭窄。