Role of LMO7 in atherosclerosis
LMO7 在动脉粥样硬化中的作用
基本信息
- 批准号:10453451
- 负责人:
- 金额:$ 53.45万
- 依托单位:
- 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:2020-08-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:Apolipoprotein EApoptosisArterial Fatty StreakArteriesAtherosclerosisBlood CirculationCardiovascular DiseasesCarotid EndarterectomyCellsCharacteristicsCholesterolCollagenDataDependenceEventExhibitsExtracellular MatrixFeedbackFunctional disorderGene ExpressionGenesHigh Fat DietHumanIn VitroInflammationInflammatoryInvestmentsKnock-outKnockout MiceLIM DomainLIM Domain ProteinLesionLipidsMapsMetalloproteasesMethodsModelingMolecularMorbidity - disease rateMorphologyMusMyocardial InfarctionNecrosisPathway interactionsPeripheral Vascular DiseasesPhenotypePlayProteinsResolutionRoleRuptureSamplingSignal PathwaySignal TransductionSmooth MuscleSmooth Muscle MyocytesSpecimenStainsStrokeTestingTherapeuticThickThinnessVascular Smooth Muscleatheroprotectiveatherosclerotic plaque rupturebiobankcoronary plaquein vivoinsightloss of functionmRNA Expressionmolecular imagingmortalitynovelpreventsingle-cell RNA sequencingtranscription factortransdifferentiationvascular injurywound healing
项目摘要
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
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Kathleen Ann Martin其他文献
Kathleen Ann Martin的其他文献
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{{ truncateString('Kathleen Ann Martin', 18)}}的其他基金
Vascular Discovery, From Genes to Medicine 2023
血管发现,从基因到医学 2023
- 批准号:
10683501 - 财政年份:2023
- 资助金额:
$ 53.45万 - 项目类别:
2022 Vascular Discovery: From Genes to Medicine
2022 年血管发现:从基因到医学
- 批准号:
10469131 - 财政年份:2022
- 资助金额:
$ 53.45万 - 项目类别:
Novel insights into intimal hyperplasia in cardiac allograft vasculopathy
对心脏同种异体移植血管病中内膜增生的新见解
- 批准号:
10090623 - 财政年份:2018
- 资助金额:
$ 53.45万 - 项目类别:
Epigenetic control of vascular smooth muscle in cardiovascular disease
心血管疾病中血管平滑肌的表观遗传控制
- 批准号:
8761918 - 财政年份:2014
- 资助金额:
$ 53.45万 - 项目类别:
Regulation of vascular smooth muscle cell plasticity
血管平滑肌细胞可塑性的调节
- 批准号:
8998052 - 财政年份:2014
- 资助金额:
$ 53.45万 - 项目类别:
Regulation of vascular smooth muscle cell plasticity
血管平滑肌细胞可塑性的调节
- 批准号:
8630004 - 财政年份:2014
- 资助金额:
$ 53.45万 - 项目类别:
Regulation of vascular smooth muscle cell plasticity
血管平滑肌细胞可塑性的调节
- 批准号:
8798690 - 财政年份:2014
- 资助金额:
$ 53.45万 - 项目类别:
Regulation of vascular smooth muscle cell plasticity
血管平滑肌细胞可塑性的调节
- 批准号:
9211370 - 财政年份:2014
- 资助金额:
$ 53.45万 - 项目类别:
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