Role of LMO7 in atherosclerosis

LMO7 在动脉粥样硬化中的作用

• 批准号: 10453451
• 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/10453451
• 关键词: Apolipoprotein E; Apoptosis; Arterial Fatty Streak; Arteries; Atherosclerosis; Blood Circulation; Cardiovascular Diseases; Carotid Endarterectomy; Cells; Characteristics; Cholesterol; 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; Proteins; 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; 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