Role of LMO7 in atherosclerosis

LMO7 在动脉粥样硬化中的作用

• 批准号: 10670757
• 负责人: Kathleen Ann Martin
• 金额: $ 53.45万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10670757
• 关键词: Apolipoprotein E; Apoptosis; Arterial Fatty Streak; Arteries; Atherosclerosis; Cardiovascular Diseases; Carotid Endarterectomy; Cd68; Cells; Characteristics; Cholesterol; Circulation; Collagen; Data; Dependence; Event; Exhibits; Extracellular Matrix; Feedback; Functional disorder; Gene Expression; Genes; High Fat Diet; Human; In Vitro; Inflammation; Inflammatory; Investments; Knock-out; Knockout Mice; LIM Domain; LIM Domain Protein; Lesion; Lipids; Maps; Metalloproteases; Methods; Modeling; Molecular; Morbidity - disease rate; Morphology; Mus; Myocardial Infarction; Necrosis; Pathway interactions; Peripheral Vascular Diseases; Phenotype; Play; Proliferating; Proteins; Repression; Resolution; Role; Rupture; Sampling; Signal Pathway; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Specimen; Stains; Stroke; Testing; Therapeutic; Thick; Thinness; Vascular Smooth Muscle; atheroprotective; atherosclerotic plaque rupture; biobank; comparison control; coronary plaque; in vivo; insight; loss of function; mRNA Expression; molecular imaging; mortality; novel; prevent; single-cell RNA sequencing; transcription factor; transdifferentiation; vascular injury; wound healing; Apolipoprotein E; Apoptosis; Arterial Fatty Streak; Arteries; Atherosclerosis; Cardiovascular Diseases; Carotid Endarterectomy; Cd68; Cells; Characteristics; Cholesterol; Circulation; Collagen; Data; Dependence; Event; Exhibits; Extracellular Matrix; Feedback; Functional disorder; Gene Expression; Genes; High Fat Diet; Human; In Vitro; Inflammation; Inflammatory; Investments; Knock-out; Knockout Mice; LIM Domain; LIM Domain Protein; Lesion; Lipids; Maps; Metalloproteases; Methods; Modeling; Molecular; Morbidity - disease rate; Morphology; Mus; Myocardial Infarction; Necrosis; Pathway interactions; Peripheral Vascular Diseases; Phenotype; Play; Proliferating; Proteins; Repression; Resolution; Role; Rupture; Sampling; Signal Pathway; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Specimen; Stains; Stroke; Testing; Therapeutic; Thick; Thinness; Vascular Smooth Muscle; atheroprotective; atherosclerotic plaque rupture; biobank; comparison control; coronary plaque; in vivo; insight; loss of function; mRNA Expression; molecular imaging; mortality; novel; prevent; single-cell RNA sequencing; transcription factor; transdifferentiation; vascular injury; wound healing

Role of LMO7 in atherosclerosis Atherosclerosis is a major cause of cardiovascular disease morbidity and mortality, including myocardial infarction (MI), stroke, and peripheral vascular disease. As plaque rupture is a key factor in atherothrombotic events, understanding the determinants of plaque stability is critical. The underlying molecular mechanisms are poorly understood, but thin cap fibroatheromas, characterized by inflammation, matrix metalloprotease (MMP) activity, large necrotic cores, and thin fibrous caps, are considered more vulnerable to rupture. Vascular smooth muscle cells (SMC) play a critical role in plaque stabilization by forming the fibrous cap that covers the lipid-laden plaque and necrotic core. Recent studies have revealed the paradigm-changing findings that SMC comprise a greater portion of the plaque interior than previously appreciated by transdifferentiating to phenotypes that lack SMC markers, and that investment of the plaque by SMC-derived cells appears to be atheroprotective. Thus, SMC play a central role in regulating both plaque size and stability. Multiple lines of evidence support a protective role for TGF signaling in plaques. We have recently identified the protein LIM Domain Only 7 (LMO7) as a key negative feedback regulator of TGF signaling in SMC that promotes wound healing resolution (Xie et al, Circulation, 2019). Mice with global or inducible smooth muscle-specific knockout of LMO7 (SM-LMO7-/-) exhibit enhanced TGF signaling and extracellular matrix (ECM) synthesis compared to controls following vascular injury. We find that LMO7 represses the TGF pathway at multiple levels. In new studies, we demonstrate that SM-LMO7-/- mice develop plaques of similar size but with features of increased stability compared to controls in the ApoE-/- high fat diet (HFD) model. The SM- LMO7-/- plaques have reduced necrotic core size, decreased CD68+ cells, increased ACTA2 and collagen staining, and thicker fibrous caps. Preliminary lineage tracing data in these mice reveals that SM-LMO7-/- increases the number of transdifferentiated SMC-derived cells in lesions, a phenotype that may be protective. Preliminary data in human carotid specimens reveals that LMO7 mRNA expression is increased 5.6X in plaque vs normal artery, and is enriched in ruptured vs non-ruptured lesions. We hypothesize that LMO7 loss of function in SMC promotes more stable plaques in mice and humans. In Aim 1, we will determine the role of SMC LMO7 in plaque composition and gene expression using comprehensive staining and single cell RNA-sequencing analyses. In Aim 2, we will dissect underlying mechanisms, and in Aim 3, we directly test the role of SMC LMO7 in lesion stability by assessing plaque rupture in mice, as well as LMO7 expression and localization in human ruptured vs stable lesions. These studies will provide insights into the pathophysiology of atherosclerotic plaque remodeling with potential therapeutic implications.

LMO7在动脉粥样硬化动脉粥样硬化中的作用是心血管疾病发病率和 死亡率，包括心肌梗塞（MI），中风和周围血管疾病。因为斑块破裂是 动脉粥样硬化事件中的关键因素，了解斑块稳定性的决定剂至关重要。 潜在的分子机制知之甚少，但是薄的帽纤维瘤，其特征是 炎症，基质金属蛋白酶（MMP）活性，较大的坏死核和薄纤维帽 更容易破裂。血管平滑肌细胞（SMC）在斑块稳定中起着至关重要的作用 形成覆盖含脂质斑块和坏死芯的纤维帽。最近的研究揭示了 SMC的范式改变的发现比以前更大的牙菌体内部 通过将缺乏SMC标记的表型转变为赞赏，而对 SMC衍生细胞的斑块似乎是动脉保护性的。那，SMC在调节中起着核心作用 斑块大小和稳定性。 多种证据支持斑块中TGF信号传导的受保护作用。我们最近有 仅确定蛋白质lim结构域7（LMO7）是SMC中TGF信号的关键负反馈调节剂 这促进了伤口愈合分辨率（Xie等，《循环》，2019年）。具有全球或诱导光滑的小鼠 LMO7（SM-LMO7 - / - ）肌肉特异性敲除暴露的增强的TGF信号和细胞外基质 （ECM）与血管损伤后对照组相比的合成。我们发现LMO7反映了TGF途径 在多个级别。在新研究中，我们证明了SM-LMO7 - / - 小鼠的大小相似，但 与APOE - / - 高脂肪饮食（HFD）模型中的对照相比，稳定性提高的特征。 SM- LMO7 - / - 斑块减少了坏死核大小，CD68+细胞降低，ACTA2和胶原蛋白增加 染色和较厚的纤维帽。这些小鼠的初步谱系跟踪数据表明SM-LMO7 - / - 增加了病变中翻译的SMC衍生细胞的数量，这种表型可能受到保护。 人颈动脉标本中的初步数据表明，斑块中LMO7 mRNA表达增加了5.6倍 vs正常伪影，并富含破裂的与未破裂的病变。我们假设LMO7功能丧失 在SMC中，在小鼠和人类中促进了更稳定的斑块。在AIM 1中，我们将确定SMC LMO7的作用 在使用综合染色和单细胞RNA测序的斑块组成和基因表达中 分析。在AIM 2中，我们将剖析潜在的机制，在AIM 3中，我们直接测试了SMC LMO7的作用 在病变稳定性中，通过评估小鼠的斑块破裂，以及人类的LMO7表达和定位 破裂与稳定病变。这些研究将提供有关动脉粥样硬化斑块的病理生理学的见解 重塑潜在的治疗意义。