a4�7 Integrin (LPAM-1) is Upregulated at Atherosclerotic Lesions and is Involved in Atherosclerosis Progression

Abstract

BACKGROUND/AIMS: Integrin activation and lymphocyte migration to the vascular intima is a key event in early atherosclerosis. α4β7 integrin (LPAM-1) and its ligand, mucosal addressin cell adhesion molecule (MAdCAM-1) are known to play an important role in homing of activated lymphocytes to gut-associated lymphoid tissues. However, it is unclear whether α4β7 integrin is involved in the pathogenesis of atherosclerosis. METHODS: The expressions of α4β7 integrin and its ligands in atherosclerosis plaques from 12 week high fat diet (HFD) fed ApoE(-/-) and C57BL/6 mice were examined using immunofluorescent and immunohistochemical assays, respectively. We also generated ApoE/β7 double deficient mice and compared atherosclerotic lesion development in β7(+/+)ApoE(-/-) and β7(-/-)ApoE(-/-) mice that were fed with HFD for 12 weeks. RESULTS: We found an upregulation of α4β7 integrin and its ligands VCAM-1 and MAdCAM-1 at atherosclerosis plaques in Apolipoprotein E deficient (ApoE(-/-)) mice fed with HFD for 12 weeks. Over the 12 week HFD period, peripheral blood lymphocyte (PBL) expression of α4β7 integrin increased in parallel with aortic lesion size. A removal of α4β7 integrin by genetic deletion of the β7 chain in the ApoE(-/-) mouse resulted in a markedly decreased 12 week-HFD atherosclerotic plaque area. β7(-/-) ApoE(-/-) macrophages showed reduced acetylated and native LDL uptake and phagocytic activity, revealing possible roles for α4β7 at two distinct stages of macrophage dysfunction during atherogenesis. Finally, a reduced activity of integrin downstream signalling components focal adhesion kinase (FAK) and MAPK/ERK1/2 in macrophage indicates their possible engagement during α4β7 integrin signalling in atherosclerosis. CONCLUSIONS: Together our results reveal a critical role of α4β7 in diet-induced atherosclerosis in mouse.