From the Department of Pathology, A.Z. Middelheim, Antwerp (M.M.K.,
J.M.), and the Division of Pharmacology (UIA) (G.R.Y. De M., H.B., A.G.H.) and
the Centre for Electron Microscopy (W.J.), University of Antwerp, Wilrijk,
Belgium.
Correspondence to Dr M. Kockx, Department of Pathology, A.Z. Middelheim, Lindendreef, 1, B-2020 Antwerp, Belgium. E-mail mark.kockx{at}uia.ua.ac.be
Background—The transition of a fatty
streak into an atherosclerotic plaque is characterized by the
appearance of focal and diffuse regions of cell death. We have
investigated the distribution of apoptotic cell death and
apoptosis-related proteins in early and advanced
atherosclerotic lesions.
Methods and Results—Human atherosclerotic plaques were studied by
whole-mount carotid endarterectomy specimens
(n=18). This approach allowed comparison of adaptive intimal
thickenings, fatty streaks, and advanced atherosclerotic plaques of the
same patient. The fatty streaks differed from adaptive intimal
thickenings by the presence of BAX (P<0.01), a
proapoptotic protein of the BCL-2 family. Both regions were
composed mainly of smooth muscle cells (SMCs), and macrophage
infiltration was low and not different. Apoptosis, as detected
by DNA in situ end labeling (terminal
deoxynucleotidyl transferase end labeling [TUNEL]
and in situ nick translation) was not present in these regions.
Apoptosis of SMCs and macrophages, however, was
present in advanced atherosclerotic plaques that were present
mainly in the carotid sinus. A dense infiltration of
macrophages (5.8±3% surface area) was present in these
advanced atherosclerotic plaques. Cytoplasmic remnants of
apoptotic SMCs, enclosed by a cage of thickened basal lamina,
were TUNEL negative and remained present in the plaques as matrix
vesicles.
Conclusions—We conclude that SMCs within human fatty streaks
express BAX, which increases the susceptibility of these cells to
undergo apoptosis. The localization of these susceptible SMCs
in the deep layer of the fatty streaks could be important in our
understanding of the transition of fatty streaks into atherosclerotic
plaques, which are characterized by regions of cell death. Matrix
vesicles are BAX-immunoreactive cytoplasmic remnants of fragmented SMCs
that can calcify and may be considered the graves of SMCs that have
died in the plaques.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Apoptosis and Related Proteins in Different Stages of Human Atherosclerotic Plaques
Key Words: atherosclerosis • apoptosis • cholesterol • carotid arteries • muscle, smooth • cells
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