APOPTOSIS OF SMOOTH MUSCLE CELLS IN CAROTID PLAQUES

颈动脉斑块中平滑肌细胞的凋亡

• 批准号: 7340390
• 负责人: Devendra K. Agrawal
• 金额: $ 24.84万
• 依托单位: CREIGHTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-08 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7340390
• 关键词: Adhesions; Affinity; Apoptosis; Apoptotic; Appendix; Arterial Fatty Streak; Atherosclerosis; Blood Vessels; Carotid Arteries; Carotid Artery Plaques; Carotid Artery Ulcerating Plaque; Carotid Stenosis; Cell Cycle; Cell Cycle Proteins; Cell Nucleus; Cells; Chemotactic Factors; Clinical; Coronary Arteriosclerosis; Cyclin D1; Cyclin E; Cyclin-Dependent Kinase Inhibitor; Data; Endarterectomy; Endothelium; Extracellular Matrix; FOXO1A gene; Family; Functional disorder; Genetic Transcription; Human; IGFBP1 gene; IGFBP2 gene; IGFBP3 gene; IGFBP4 gene; Immune system; In Situ Nick-End Labeling; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor Binding Protein 4; Insulin-Like Growth Factor I; Insulin-Like Growth-Factor Binding Protein 1; Insulin-Like-Growth Factor I Receptor; Intercellular adhesion molecule 1; Interferon Type II; Interferons; Interleukin-12; Interleukin-18; Label; Laboratories; Lead; Lipids; Lymphocyte; Morbidity - disease rate; Nebraska; Necrosis; Neurologic; Numbers; Organ Retrievals; Patients; Phase; Proliferating; Proteins; Reporting; Role; Running; Rupture; Smooth Muscle Myocytes; Somatomedins; Specimen; Symptoms; System; T-Lymphocyte; Thick; Thrombus; Time; Translations; Vascular Diseases; Video Microscopy; annexin A5; caspase-3; cost; cytokine; density; forkhead protein; inhibitor/antagonist; macrophage; member; monocyte; mortality; p27 Cell Cycle Protein; p27 Enzyme Inhibitor; transcription factor

DESCRIPTION (provided by applicant): Morbidity and mortality from atherosclerosis are associated with complicated atherosclerotic lesions due to plaque rupture and severe hemispheric neurological symptoms. However, a group of atherosclerotic patients remain asymptomatic because of plaque stability. It is not known if and how the stable and unstable plaques are different biochemically, and how the immune system regulates plaque stability. The studies over the past several years in our laboratory suggest that insulin-like growth factor-1 (IGF-1) is a potent chemoattractant for monocytes, and possess strong mitogenic and anti-apoptotic activity for vascular smooth muscle cells (VSMCs). Furthermore, we have shown that in stable plaques there is increased density of VSMCs and decreased number of macrophages and T-lymphocytes, whereas reverse is true with unstable plaques. We propose the hypothesis that decreased expression and activity of IGF-1 receptors (IGF-1R) on VSMCs due to cytokines released by proliferating and activated T-lymphocytes (IFN-gamma) and macrophages (IL-12 and IL-18) leads to apoptosis resulting in the instability of atherosclerotic plaques observed in symptomatic patients. To these ends the Specific Aims of this application in the carotid plaque VSMCs of both symptomatic and asymptomatic patients are: Specific Aim 1: We will examine IGF-l-induced survival of plaque VSMCs of both symptomatic and asymptomatic patients in the presence and absence of human atheroma-associated cytokines (11-12, IL-18 and IFN-gamma) using TUNEL, annexin V labeling, time-lapse videomicroscopy, and caspase 3 activity. For comparison, VSMCs from normal carotid artery will be run in parallel. Specific Aim 2: We will examine the underlying mechanisms of cytokine-induced decrease in IGF-l-induced survival of VSMCs. We will assess the effect of cytokines on IGF-1R and IGFBPs in VSMCs of symptomatic and asymptomatic carotid plaques. Specific Aim 3: We will investigate the role of FoxO family of forkhead transcription factors, specifically FKHR (FoxO1) and FKHR-L1 (FoxO3), and cyclin-dependent kinase inhibitor p27kip1 and Bim, a pro-apoptotic proteinof Bcl-2 family in IGF-l-induced survival of VSMCs from symptomatic and asymptomatic carotid plaques. A better understanding of the pathophysiology of carotid stenosis and regulatory role of IGF-1 receptors in the stability of plaques will provide opportunities to develop a more precise and cost-effective treatment.

描述（由申请人提供）：动脉粥样硬化的发病率和死亡率与斑块破裂和严重半球神经症状引起的复杂动脉粥样硬化病变相关。然而，一组动脉粥样硬化患者由于斑块的稳定性而保持无症状。目前尚不清楚稳定和不稳定斑块是否以及如何在生物化学上不同，以及免疫系统如何调节斑块稳定性。本实验室近几年的研究表明，胰岛素样生长因子-1（insulin-like growth factor-1，IGF-1）是一种强有力的单核细胞趋化因子，对血管平滑肌细胞（vascular smooth muscle cells，VSMCs）具有较强的促有丝分裂和抗凋亡活性。此外，我们已经表明，在稳定的斑块中，VSMCs的密度增加，巨噬细胞和T淋巴细胞的数量减少，而不稳定的斑块则相反。我们提出的假设是，由于增殖和活化的T淋巴细胞（IFN-γ）和巨噬细胞（IL-12和IL-18）释放的细胞因子导致VSMCs上IGF-1受体（IGF-1 R）的表达和活性降低，导致细胞凋亡，导致在有症状的患者中观察到的动脉粥样硬化斑块的不稳定性。为此，本申请在有症状和无症状患者的颈动脉斑块VSMC中的具体目的是：具体目的1：我们将研究在存在和不存在人类动脉粥样硬化相关细胞因子的情况下，IGF-1诱导的有症状和无症状患者斑块VSMC的存活。（11-12，IL-18和IFN-γ），使用TUNEL，膜联蛋白V标记，延时视频显微镜和半胱天冬酶3活性。为了比较，将平行运行来自正常颈动脉的VSMC。具体目标2：我们将检查马槟榔碱诱导的IGF-1诱导的VSMC存活减少的潜在机制。我们将评估细胞因子对有症状和无症状颈动脉斑块的VSMCs中IGF-1 R和IGFBPs的影响。具体目标3：我们将研究FoxO家族的叉头转录因子，特别是FKHR（FoxO 1）和FKHR-L1（FoxO 3），以及细胞周期蛋白依赖性激酶抑制剂p27 kip 1和Bcl-2家族的促凋亡蛋白Bim在IGF-1诱导的有症状和无症状颈动脉斑块的VSMC存活中的作用。更好地了解颈动脉狭窄的病理生理学和IGF-1受体在斑块稳定性中的调节作用，将为开发更精确和更具成本效益的治疗提供机会。