miRNA-mediated reduction of VSMC foam cell formation

miRNA 介导的 VSMC 泡沫细胞形成减少

基本信息

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
项目类别：
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

项目摘要

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，导致斑块增加大小和稳定性降低是动脉粥样硬化中的关键，但研究了。我们在上一个资金周期（HL117724）表明，介绍（IL-19）是一种新颖的抗炎细胞因子，通过对VSMC和增加脂质的多种抗炎作用来减轻动脉粥样硬化巨噬细胞中的吸收和外排。在此处描述的出版和初步研究中，我们表明IL-19 减少脂质在VSMC中的积累，VSMC是一种动脉保护事件，但没有改变脂质的表达受体或转运蛋白。 IL-19诱导miR133a的表达，以前是一种肌肉特异性miRNA 归因于调节VSMC表型。尽管未被认可和未经报告，但我们已经确定 miR133a可以靶向并减少低密度脂蛋白受体适配器蛋白1的表达，（LDLRAP1），一种衔接蛋白，可将LDL受体内化。突变患者 LDLRAP1具有LDL受体故障，导致高脂血症和常染色体隐性高胆固醇血症（ARH）疾病。关于mir133a在调节中的作用，根本没有任何了解脂质摄取和动脉粥样硬化的发展。同样，什么都没有发表 LDLRAP1表达，功能和参与VSMC泡沫细胞形成。我们报告了 MiR133a和LDLRAP1都调节VSMC中的OXLDL吸收。 ldlrap1在oxldl中诱导的VSMC诱导，在正常内侧VSMC中无法检测到，但在受伤的动脉的牙菌斑和新内膜VSMC中表达。 IL-19可以减少VSMC中的LDLRAP1表达和OXLDL吸收。 mir133a和ldlrap1 regunder VSMC增殖，这些分子以前未被认可的功能。初步研究表明 ldlrap1 +/-小鼠增加了动脉粥样硬化，但减少了再狭窄。在这种竞争中续订应用，我们假设在VSMC中可以选择性地降低LDLRAP1，因为MiR133a 是特定于肌肉的，VSMC降低脂质的摄取是动脉保护性的，也可能衰减血管增殖综合征。该应用程序的总体目标是确定 MiR133a和LDLRAP1在VSMC脂质摄取，增殖，动脉粥样硬化，胆固醇诱导的表型中调节和血管再狭窄。