From the Department of Internal Medicine (S.S.P., R.T., J.T.W., E.T.H.Y.)
and the Institute of Molecular Medicine for the Prevention of Human Diseases
(E.T.H.Y.), University of Texas Health Sciences Center, Houston, Tex; and the
Texas Heart Institute (J.T.W., E.T.H.Y.), St Luke's Episcopal Hospital,
Houston, Tex.
Correspondence to E.T.H. Yeh, Department of Internal Medicine, 6431 Fannin, Suite 4200, UT-Houston HSC, Houston, TX 77030.
Background—Monocytes/macrophages
play a central role in many stages of development of atherosclerotic
plaques, including the conversion to an unstable morphology with
rupture and fissuring. A better understanding of the mechanism of
attachment of monocytes to activated
endothelial cells would prove useful in developing
strategies aimed at blocking this initial step. Here we describe a
novel in vivo model that directly demonstrates homing of
macrophages to atherosclerotic plaques.
Methods and Results—Macrophages were loaded with
fluorescent microspheres and injected
intravenously into 40-week-old apolipoprotein E–deficient
mice. After 48 hours, labeled macrophages were observed
adhering to all stages of atherosclerotic plaques from the early fatty
streak to mature calcified lesion. The mean number of
macrophages adherent to atherosclerotic plaques located in the
proximal 1 mm of the aortic root was quantitated by counting
serial frozen sections and found to be 143±17 macrophages per
aortic root. Pretreatment of the apolipoprotein E–deficient mice with
monoclonal antibodies directed against the
Conclusions—These data demonstrate that
© 1998 American Heart Association, Inc.
Basic Science Reports
Inhibition of
4 Integrin and ICAM-1 Markedly Attenuate Macrophage Homing to Atherosclerotic Plaques in ApoE-Deficient Mice
-subunit of the
4ß1 integrin and against intracellular
cell adhesion molecule (ICAM-1) reduced macrophage homing by
75% and 65%, respectively, as compared with isotype-matched controls
(P<.05). Pretreatment with a monoclonal antibody
directed against E-selectin did not significantly reduce
macrophage homing. 4 integrin
and ICAM-1 play major roles in the recruitment of macrophages
to atherosclerotic plaques, whereas E-selectin does not appear to
contribute significantly to macrophage recruitment. This model
will be useful for studying the mechanism of macrophage
recruitment to atherosclerotic plaques and for evaluating the efficacy
of inhibitors to adhesion molecules in preventing
macrophage recruitment.
Key Words: atherosclerosis • monocytes • macrophages • cells • adhesion • molecules • integrins
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