LncRNA MAARS, macrophage apoptosis, and atherosclerosis

LncRNA MAARS、巨噬细胞凋亡和动脉粥样硬化

基本信息

批准号：
10626018
负责人：
MARK W FEINBERG
金额：
$ 41.59万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10626018
关键词：
Address Affect Aorta Apoptosis Apoptosis Regulation Gene Apoptotic Arterial Fatty Streak Atherosclerosis Attention Biological Assay Biological Process Biophysics Bone Marrow CASP3 gene Carotid Artery Diseases Cause of Death Cell Death Cell physiology Cells Characteristics Chromatin Remodeling Factor Chronic Code Cytoplasm Data Dependence Detection Disease Disease Progression Event Foundations Genes Goals Homologous Gene Human In Vitro Induction of Apoptosis Kinetics Knockout Mice Lesion Link Lipids Longitudinal Studies Macrophage Mediating Molecular Mus Mutation Myocardial Infarction Necrosis Nuclear Peripheral Blood Mononuclear Cell Peripheral Vascular Diseases Phase Play Poly A Polyadenylation Process Proteins RNA RNA Sequences RNA-Binding Proteins Regulation Role Signal Pathway Signal Transduction Splenocyte Stains Stimulus Stroke Therapeutic Untranslated RNA Vascular Diseases Work atherogenesis genetic signature improved in vivo inhibitor insight knock-down mRNA Stability new therapeutic target novel novel therapeutic intervention therapeutic RNA trafficking transcriptome sequencing

项目摘要

Atherosclerosis, a chronic arterial disease, involves multiple cellular processes including the accumulation of intimal macrophages. Macrophage apoptosis is increased with progression of atherosclerosis, leading to increased cell death and accumulation of cellular debris. This in turn may abrogate macrophage efferocytosis, an important event for clearance of apoptotic or necrotic cells. Therefore, improving the efficiency of macrophages in the clearance of intra-lesional cellular debris may provide a novel therapeutic approach to limit atherosclerotic progression. Long non-coding RNAs (lncRNAs) have garnered widespread attention as emerging regulators of diverse biological processes relevant to atherosclerosis. However, the identity and roles of specific lncRNAs within atherosclerotic lesions are not well defined. Using RNA-Seq profiling to identify lncRNAs derived specifically from the aortic intima of LDLR-/- mice during lesion progression and regression phases, we identify the lncRNA MAARS (Macrophage-Associated Atherosclerosis lncRNA Sequence). MAARS was the highest expressed lncRNA with a 300-fold increase after lesion progression and decreased by 70% with regression. MAARS is a polyadenylated, macrophage- and nuclear-specific, lncRNA. Kinetic studies showed that MAARS expression is markedly induced in macrophages differentiated from bone marrow, PBMCs, or splenocytes. Our preliminary data demonstrate that systemic delivery of inhibitors to MAARS strongly reduced lesion size, independent of effects on circulating lipid profile, but rather by decreased macrophage apoptosis and increased efferocytosis in the vessel wall. Deficiency of MAARS reduced macrophage apoptosis induced by different stimuli and increased macrophage efferocytosis in vitro. Mechanistically, lncRNA pulldown assays in combination with LC-MS/MS analysis showed that MAARS interacts with HuR, an RNA-binding protein and important regulator of apoptosis. Preliminary studies show that HuR silencing increases macrophage apoptosis and that the MAARS-mediated effects on macrophage apoptosis may be HuR dependent. In addition, MAARS knockdown altered HuR nuclear-cytoplasmic trafficking, and regulated important apoptotic genes. These observations provide the foundation for the central hypothesis that MAARS deficiency, via regulatory effects on HuR and specific macrophage apoptotic signaling pathways, reduces macrophage apoptosis, improves cellular efferocytosis, and suppresses atherosclerosis. To address this further, in Aim1 we examine the role of MAARS in regulating HuR-mediated macrophage apoptosis and efferocytosis; in Aim2, we assess how alterations of MAARS expression affects short- and long-term atherosclerosis in vivo; and in Aim3, we examine the role of the MAARS-HuR signaling axis in human cells and atherosclerotic lesions. Our studies will address a major gap in our understanding of lncRNAs in atherosclerosis and inform how MAARS-mediated control of macrophage apoptosis and efferocytosis may provide new targets for therapy.

动脉粥样硬化是一种慢性动脉疾病，涉及多个细胞过程内膜巨噬细胞。随着动脉粥样硬化的进展，巨噬细胞凋亡增加，导致细胞死亡增加和细胞碎片的积累。反过来，这可能消除巨噬细胞的吞噬作用，清除凋亡或坏死细胞的重要事件。因此，提高效率巨噬细胞在清除的巨噬细胞内碎片碎片中可能会提供一种新型的治疗方法来限制动脉粥样硬化进展。长期非编码RNA（LNCRNA）作为新兴的调节剂引起了广泛关注与动脉粥样硬化有关的多种生物过程。但是，特定lncrnas的身份和角色在动脉粥样硬化中，病变的定义不当。使用RNA-seq分析来识别得出的lncRNA 特别是在病变进展和回归阶段的LDLR - / - 小鼠的主动脉内膜中，我们确定 LNCRNA MAAR（巨噬细胞相关的动脉粥样硬化lncRNA序列）。 Maars是最高的在病变进展后表达lncRNA，增加了300倍，随着回归的速度降低了70％。 MAARS是一种多腺苷酸化的，巨噬细胞和核特异性的lncRNA。动力学研究表明MAAR 在与骨髓，PBMC或脾细胞区分的巨噬细胞中明显诱导的表达。我们的初步数据表明，将抑制剂的全身性递送到MAARS上大大降低了病变的大小，独立于对循环脂质剖面的影响，而是通过减少巨噬细胞凋亡和血管壁中的递增细胞增多症增加。 MAAR的缺乏降低了巨噬细胞的凋亡不同刺激和体外巨噬细胞肿瘤的增加。从机械上讲，lncrna ulldown分析与LC-MS/MS分析的结合表明，MAARS与HUR相互作用，RNA结合蛋白和凋亡的重要调节剂。初步研究表明，HUR沉默会增加巨噬细胞的凋亡并且MAARS介导的对巨噬细胞凋亡的影响可能取决于HUR。此外，Maars 敲低改变了HUR核胞质运输，并调节了重要的凋亡基因。这些观察为中心假设奠定了基础，即MaARS缺乏，通过调节作用 HUR和特定巨噬细胞凋亡信号通路，减少巨噬细胞凋亡，改善细胞肿瘤病并抑制动脉粥样硬化。为了进一步解决这个问题，在AIM1中，我们研究了MAAR的作用在调节HUR介导的巨噬细胞凋亡和吞噬作用方面；在AIM2中，我们评估了如何改变 MAARS表达会影响体内的短期和长期动脉粥样硬化。在AIM3中，我们研究了人类细胞和动脉粥样硬化病变中的maars-hur信号轴。我们的研究将解决一个专业我们对动脉粥样硬化中LNCRNA的理解的差距，并告知MAARS介导的控制巨噬细胞的凋亡和肿瘤病可能为治疗提供新的靶标。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Methotrexate attenuates vascular inflammation through an adenosine-microRNA-dependent pathway.

DOI：
10.7554/elife.58064
发表时间：
2021-01-08
期刊：
eLife
影响因子：
7.7
作者：
Yang D;Haemmig S;Zhou H;Pérez-Cremades D;Sun X;Chen L;Li J;Haneo-Mejia J;Yang T;Hollan I;Feinberg MW
通讯作者：
Feinberg MW

Deficiency of miR-409-3p improves myocardial neovascularization and function through modulation of DNAJB9/p38 MAPK signaling.

DOI：
10.1016/j.omtn.2023.05.021
发表时间：
2023-06-13
期刊：
MOLECULAR THERAPY NUCLEIC ACIDS
影响因子：
0
作者：
Bestepe, Furkan;Fritsche, Colette;Lakhotiya, Kartik;Niosi, Carolyn E.;Ghanem, George F.;Martin, Gregory L.;Pal-Ghosh, Ruma;Becker-Greene, Dakota;Weston, James;Hollan, Ivana;Risnes, Ivar;Rynning, Stein Erik;Solheim, Liv Heidi;Feinberg, Mark W.;Blanton, Robert M.;Icli, Basak
通讯作者：
Icli, Basak

Revisiting Hormonal Control of Vascular Injury and Repair.