miRNA-mediated reduction of VSMC foam cell formation

血管平滑肌细胞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形成中的一个关键步骤，但尚未得到充分研究。我们在前一年的工作 Funding Cycle(HL117724)研究表明，白介素19(IL-19)是一种新型的抗炎细胞因子， 通过对VSMC的多种抗炎作用以及通过增加血脂来减轻动脉粥样硬化 巨噬细胞的摄取和外排。在已发表的和这里描述的初步研究中，我们表明IL-19 减少VSMC中的脂质堆积，这是一种动脉粥样硬化保护事件，但不改变脂质的表达 受体或转运体。IL-19诱导肌肉特异性miRNA miR133a的表达 被认为是对VSMC表型的调节。尽管没有被识别和报告，但我们已经确认 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)，一种连接蛋白，功能是内化低密度脂蛋白受体。存在基因突变的患者 LDLRAP1低密度脂蛋白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)。目前对miR133a在细胞周期调控中的作用一无所知。 脂质摄取与动脉粥样硬化的发展。同样，也根本没有发表过任何关于 LDLRAP1的表达、功能及其参与VSMC泡沫细胞形成的研究我们已经报道过， MiR133a和LDLRAP1都调节VSMC对oxLDL的摄取。氧化低密度脂蛋白诱导VSMC中LDLRAP1的表达 在正常的内侧VSMC中未检测到，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LDLRAP1的表达和oxLDL摄取。MiR133a和LDLRAP1均可调节 VSMC增殖，以前未知的这些分子的功能。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。在这场竞争中 续订申请，我们假设LDLRAP1在VSMC中可以选择性地减少，因为miR133a 是肌肉特异性，VSMC对脂质摄取的减少是动脉粥样硬化保护的，也可以减弱 血管增生性综合征。这个应用程序的总体目标是确定 MiR133a和LDLRAP1在VSMC脂质摄取、增殖、动脉粥样硬化形成、胆固醇诱导表型中的作用 调节和血管再狭窄。

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.