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

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 在动脉粥样硬化中的作用 动脉粥样硬化是心血管疾病发病率和发病率的主要原因 死亡率，包括心肌梗塞（MI）、中风和外周血管疾病。由于斑块破裂是 斑块是动脉粥样硬化血栓事件的关键因素，了解斑块稳定性的决定因素至关重要。这 潜在的分子机制尚不清楚，但薄帽纤维粥样硬化的特征是 考虑到炎症、基质金属蛋白酶 (MMP) 活性、大坏死核心和薄纤维帽 更容易破裂。血管平滑肌细胞 (SMC) 通过以下方式在斑块稳定中发挥关键作用： 形成覆盖载脂斑块和坏死核心的纤维帽。最近的研究表明 改变范式的发现表明 SMC 比以前占斑块内部的比例更大 通过转分化为缺乏 SMC 标记的表型而受到赞赏，并且 SMC 衍生细胞形成的斑块似乎具有动脉粥样硬化保护作用。因此，SMC在调节中发挥着核心作用。 斑块大小和稳定性。 多种证据支持 TGF 信号在斑块中的保护作用。我们最近有 确定蛋白质 LIM Domain Only 7 (LMO7) 是 SMC 中 TGF 信号传导的关键负反馈调节因子 促进伤口愈合（Xie et al, Circulation, 2019）。具有全局性或诱导性平滑肌的小鼠 肌肉特异性敲除 LMO7 (SM-LMO7-/-) 表现出增强的 TGF 信号传导和细胞外基质 （ECM）合成与血管损伤后的对照进行比较。我们发现 LMO7 抑制 TGF 通路 在多个层面上。在新的研究中，我们证明 SM-LMO7-/- 小鼠会形成大小相似的斑块，但 与 ApoE-/- 高脂肪饮食 (HFD) 模型中的对照相比，具有稳定性增强的特点。 SM- LMO7-/- 斑块减少了坏死核心的大小，减少了 CD68+ 细胞，增加了 ACTA2 和胶原蛋白 染色和较厚的纤维帽。这些小鼠的初步谱系追踪数据表明 SM-LMO7-/- 增加病变中转分化的 SMC 衍生细胞的数量，这种表型可能具有保护作用。 人类颈动脉标本的初步数据显示，斑块中 LMO7 mRNA 表达增加了 5.6 倍 与正常动脉相比，并且在破裂病变与非破裂病变中丰富。我们假设 LMO7 功能丧失 SMC 中的成分可促进小鼠和人类的斑块更加稳定。在目标 1 中，我们将确定 SMC LMO7 的作用 使用综合染色和单细胞 RNA 测序研究斑块组成和基因表达 分析。在目标2中，我们将剖析底层机制，在目标3中，我们直接测试SMC LMO7的作用 通过评估小鼠斑块破裂以及人类 LMO7 表达和定位来评估病变稳定性 破裂的病变与稳定的病变。这些研究将为动脉粥样硬化斑块的病理生理学提供见解 具有潜在治疗意义的重塑。

项目成果

The age of bone marrow dictates the clonality of smooth muscle-derived cells in atherosclerotic plaques.

• DOI: 10.1038/s43587-022-00342-5
• 发表时间: 2023-01
• 期刊: NATURE AGING
• 作者: Kabir, Inamul;Zhang, Xinbo;Dave, Jui M. M.;Chakraborty, Raja;Qu, Rihao;Chandran, Rachana R. R.;Ntokou, Aglaia;Gallardo-Vara, Eunate;Aryal, Binod;Rotllan, Noemi;Garcia-Milian, Rolando;Hwa, John;Kluger, Yuval;Martin, Kathleen A. A.;Fernandez-Hernando, Carlos;Greif, Daniel M. M.
• 通讯作者: Greif, Daniel M. M.

Targeting smooth muscle cell phenotypic switching in vascular disease.

• DOI: 10.1016/j.jvssci.2021.04.001
• 发表时间: 2021
• 期刊: JVS-vascular science
• 作者: Chakraborty R;Chatterjee P;Dave JM;Ostriker AC;Greif DM;Rzucidlo EM;Martin KA
• 通讯作者: Martin KA