Role of LMO7 in atherosclerosis

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 死亡率，包括心肌梗塞(MI)、中风和外周血管疾病。因为斑块破裂是一种 在动脉粥样硬化血栓形成事件中的关键因素，了解斑块稳定性的决定因素至关重要。这个 潜在的分子机制知之甚少，但薄帽纤维动脉粥样硬化瘤的特征是 炎症、基质金属蛋白酶(MMPs)活性、大的坏死核和薄的纤维帽被考虑在内。 更容易破裂。血管平滑肌细胞(SMC)通过以下途径在斑块稳定中发挥关键作用 形成覆盖富含脂质的斑块和坏死核心的纤维帽。最近的研究表明， 与以前相比，SMC在斑块内部所占的比例更大，这一改变范式的发现 通过向缺乏SMC标记的表型的转化而受到赞赏，以及 SMC来源的细胞形成的斑块似乎具有动脉粥样硬化保护作用。因此，SMC在调节中起着核心作用 斑块大小和稳定性。 多条证据支持斑块中转化生长因子信号的保护作用。我们最近做了 LIM结构域7(Lmo7)是转化生长因子信号的负反馈调节因子 这促进了伤口愈合的解决(谢等人，《循环》，2019年)。具有全局或可诱导平滑的小鼠 肌肉特异性敲除Lmo7(SM-Lmo7-/-)增强转化生长因子信号和细胞外基质 血管损伤后(ECM)合成与对照组比较。我们发现Lmo7抑制转化生长因子途径 在多个层面上。在新的研究中，我们证明了SM-LMO7-/-小鼠出现了类似大小的斑块，但 与ApoE/高脂饮食(HFD)模型中的对照组相比，该模型具有更高的稳定性。SM- LMO7-/-斑块缩小了坏死灶的大小，减少了CD68细胞，增加了ACTA2和胶原 染色，纤维帽较厚。这些小鼠的初步谱系追踪数据显示，SM-LMO7-/- 增加病变中转分化的SMC来源细胞的数量，这是一种可能具有保护性的表型。 人颈动脉标本的初步数据显示，LMO7mRNA在斑块中的表达增加了5.6倍 VS正常动脉，并在破裂病变与未破裂病变中丰富。我们假设LMO7功能丧失 在SMC中，促进小鼠和人类体内更稳定的斑块。在目标1中，我们将确定SMC LMO7的作用 斑块组成和基因表达的综合染色和单细胞RNA测序 分析。在目标2中，我们将剖析潜在的机制，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LMO7在人类中的表达和定位来评价病变稳定性 破裂病变与稳定病变。这些研究将为动脉粥样硬化斑块的病理生理学提供深入的认识。 具有潜在治疗意义的重塑。

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.