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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