There is considerable evidence supporting a causal role for T-lymphocytes, monocytes, and monocytederivedmacrophages in the initiation, progression, and complications of the atherosclerosis in man aswell as in experimental models. Plaque rupture is thought to be the trigger event for acute coronarysyndromes in man, and several mouse models of plaque rupture have recently been described. Lesionmacrophages 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 inexperimental atherosclerosis, particularly in the rupture-prone shoulder. Moreover, adhesion receptorsmay also regulate critical functions of emigrated leukocytes resident in lesions, including activation andsurvival. Thus, the adhesion molecules that mediate monocyte trafficking into the arterial wall a potentiallyattractive target in advanced as well as early disease.Studies to date of human and experimental lesionssuggest 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 ofestablished atherosclerosis or its late complications such as plaque rupture. Since antagonists of VLA-4have already progressed to clinical trials in other indications, the importance of VLA-4 and VCAM-1interactions in the progression and late complications of atherosclerosis is a clinically relevant question aspatients 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-lymphocyterecruitment to advanced as well as early lesions and that disruption of these adhesion pathways willreduce progression of established lesions and prevent plaque rupture. In order to test this hypothesis, wewill utilize a recently developed mouse model in which interferon-induced Cre-loxP-mediated deletion ofthe ot4 gene can be achieved at any time post-natal. These a4-deleted animals will be studied in both theApoE-/- (Aim 1) and LDRL-/- (Aim 2) background, allowing us to define for the first time the contribution ofVLA-4 in the progression of established lesions and plaque rupture as well as in lesion initiation. Tocomplement the VLA-4 studies, we will also examine the role of VCAM-1 in lesion initiation/progression ina model of conditional knockout of endothelial VCAM-1 (Aim 3).
Showing the most recent 10 out of 632 publications
