VLA-4 and VCAM-1 in Advanced Atherosclerosis

VLA-4 和 VCAM-1 在晚期动脉粥样硬化中的作用

• 批准号: 7140037
• 负责人: JOHN Marshall HARLAN
• 金额: $ 24.84万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140037
• 关键词: T lymphocyte; atherosclerosis; atherosclerotic plaque; cell cell interaction; cell type; extracellular; gene expression; intracellular; laboratory mouse; lead; lipids; macrophage; monocyte; pathologic process; smooth muscle; vascular cell adhesion molecule

There is considerable evidence supporting a causal role for T-lymphocytes, monocytes, and monocytederived macrophages in the initiation, progression, and complications of the atherosclerosis in man as well as in experimental models. Plaque rupture is thought to be the trigger event for acute coronary syndromes in man, and several mouse models of plaque rupture have recently been described. Lesion macrophages in particular have been implicated in plaque rupture by releasing de-stabilizing proteases. Notably, there is evidence for continued recruitment of circulating monocytes into arterial lesions in experimental atherosclerosis, particularly in the rupture-prone shoulder. Moreover, adhesion receptors may also regulate critical functions of emigrated leukocytes resident in lesions, including activation and survival. Thus, the adhesion molecules that mediate monocyte trafficking into the arterial wall a potentially attractive target in advanced as well as early disease.Studies to date of human and experimental lesions suggest a significant role for endothelial VCAM-1 and its major leukocyte counter-receptor VLA-4 (cc4(31) in the early phase of disease, but have not examined the role of VLA-4 or VCAM-1 in the progression of established atherosclerosis or its late complications such as plaque rupture. Since antagonists of VLA-4 have already progressed to clinical trials in other indications, the importance of VLA-4 and VCAM-1 interactions in the progression and late complications of atherosclerosis is a clinically relevant question as patients are most often identified in this stage of the disease. We hypothesize that the VLA-4 and VCAM-1 play important roles in monocyte and T-lymphocyte recruitment to advanced as well as early lesions and that disruption of these adhesion pathways will reduce progression of established lesions and prevent plaque rupture. In order to test this hypothesis, we will utilize a recently developed mouse model in which interferon-induced Cre-loxP-mediated deletion of the ot4 gene can be achieved at any time post-natal. These a4-deleted animals will be studied in both the ApoE-/- (Aim 1) and LDRL-/- (Aim 2) background, allowing us to define for the first time the contribution of VLA-4 in the progression of established lesions and plaque rupture as well as in lesion initiation. To complement the VLA-4 studies, we will also examine the role of VCAM-1 in lesion initiation/progression in a model of conditional knockout of endothelial VCAM-1 (Aim 3).

大量证据支持T淋巴细胞、单核细胞和单核细胞源性 巨噬细胞在人类动脉粥样硬化的发生、发展和并发症中的作用 在实验模型中也是如此。斑块破裂被认为是急性冠状动脉粥样硬化的触发事件， 最近已经描述了人的综合征和几种斑块破裂的小鼠模型。病变 特别是巨噬细胞通过释放去稳定化蛋白酶而与斑块破裂有关。 值得注意的是，有证据表明循环单核细胞持续募集到动脉病变中， 实验性动脉粥样硬化，特别是在易破裂的肩部。此外，粘附受体 还可以调节驻留在病变中的移出的白细胞的关键功能，包括激活和 生存因此，介导单核细胞运输到动脉壁的粘附分子可能是一种潜在的细胞因子。 在晚期和早期疾病中是有吸引力的靶点。 提示内皮VCAM-1及其主要白细胞反受体VLA-4（α 4）具有重要作用（31）， 在疾病的早期阶段，但尚未检查VLA-4或VCAM-1在疾病进展中的作用。 确定的动脉粥样硬化或其晚期并发症，如斑块破裂。由于VLA-4的拮抗剂 已经进展到其他适应症的临床试验，VLA-4和VCAM-1的重要性 动脉粥样硬化进展和晚期并发症的相互作用是一个临床相关问题， 患者最常在疾病的这个阶段被识别。 我们推测VLA-4和VCAM-1在单核细胞和T淋巴细胞中起重要作用 募集到晚期和早期病变，这些粘连通路的破坏将 减少已形成的病变的进展并防止斑块破裂。为了验证这个假设，我们 将利用最近开发的小鼠模型，其中干扰素诱导的Cre-loxP-介导的 ot 4基因可以在出生后的任何时间获得。这些a4缺失的动物将在两个实验中进行研究。 ApoE-/-（目标1）和LDRL-/-（目标2）背景，使我们能够首次定义 VLA-4在已建立的病变和斑块破裂的进展中以及在病变开始中的作用。到 作为对VLA-4研究的补充，我们还将研究VCAM-1在以下疾病中的病变起始/进展中的作用： 内皮VCAM-1的条件性敲除模型（Aim 3）。