VLA-4 and VCAM-1 in Advanced Atherosclerosis

有相当多的证据支持T淋巴细胞、单核细胞和单核细胞来源的因果关系 巨噬细胞在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病变的触发事件 最近描述了人类的症状和几种斑块破裂的小鼠模型。损伤 巨噬细胞通过释放不稳定的蛋白水解酶参与斑块破裂。 值得注意的是，有证据表明循环中的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，黏附受体 也可以调节驻留在病变中的移居的白细胞的关键功能，包括激活和 生死存亡。因此，介导单核细胞进入动脉壁的黏附分子有可能 晚期和早期疾病中有吸引力的靶点：迄今对人类和实验性病变的研究 提示内皮细胞VCAM-1及其主要的白细胞对抗受体VLA-4(CC4(31))具有重要作用 在疾病的早期阶段，但没有研究VLA-4或VCAM-1在疾病进展中的作用 已确诊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 已经在其他适应症上进行了临床试验，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的问题，如 患者通常是在疾病的这个阶段被发现的。 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 对晚期和早期损伤以及这些粘连通路的破坏将 减少已建立的病变的进展，防止斑块破裂。为了检验这一假设，我们 将利用最近开发的一种小鼠模型，在该模型中，干扰素诱导的Cre-loxP介导的 Ot4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 APOE-/-(目标1)和LDRL-/-(目标2)背景，使我们能够第一次定义 VLA-4在已建立的病变和斑块破裂的进展中以及在病变起始中的作用。至 作为对VLA-4研究的补充，我们还将研究VCAM-1在血管内皮细胞损伤发生/发展中的作用。 内皮细胞VCAM-1条件性基因敲除模型(目标3)。

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).