(Circulation. 1999;99:96-104.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Death of Smooth Muscle Cells and Expression of Mediators of Apoptosis by T Lymphocytes in Human Abdominal Aortic Aneurysms
From the Cardiovascular Division, Department of Medicine, Vascular Medicine and Atherosclerosis Unit (E.L.H., G.K.S., P.L.), and Division of Vascular Surgery, Department of Surgery (A.D.W., J.K.), Brigham and Women's Hospital, Harvard Medical School, Boston, Mass, and the Cardiovascular and Pulmonary Research Institute, Allegheny University of the Health Sciences, Pittsburgh, Pa (Y.-J.G.).
Correspondence to Peter Libby, MD, Vascular Medicine and Atherosclerosis Unit, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Ave, LMRC 307, Boston, MA 02115. E-mail plibby{at}rics.bwh.harvard.edu
Background—Thinning of the tunica media and rarefaction of smooth muscle cells (SMCs) characterize aneurysmal aortas. Apoptosis determines the cellularity and morphogenesis of tissue. Macrophages and T lymphocytes infiltrate the wall of abdominal aortic aneurysms (AAAs) and produce death-promoting proteins (perforin, Fas, and FasL). This study investigated whether apoptosis occurs in association with the expression of these proteins.
Methods and Results—We examined signs of apoptosis and
expression of death-promoting mediators in segments of AAAs from
patients undergoing elective repair (n=20). Anti–
-actin
immunostaining showed a reduced number of SMCs in AAAs.
In situ terminal transferase-mediated dUTP nick end-labeling (TUNEL)
showed higher levels of DNA fragmentation in AAAs than in controls
(n=5). The AAA walls contained more cells bearing markers of
apoptosis than normal aorta (P<0.05, Student's
t test). Double immunostaining
identified SMCs and macrophages as the principal cell types
displaying fragmented DNA. Immunohistochemistry revealed that AAAs but
not normal aorta contained CD4+ and CD8+ T
cells that expressed well-characterized cytotoxic mediators: perforin,
which produces membrane damage, and Fas, which acts by ligand-receptor
interaction. Double immunostaining also identified SMCs
that expressed Fas. Immunoblotting confirmed the
presence and, in the case of Fas, activation of these proteins in
aneurysmal tissue.
Conclusions—Many medial SMCs in AAAs bear markers of apoptosis and signals capable of initiating cell death. Apoptotic death may contribute to the reduction of cellularity and to the impaired repair and maintenance of the arterial extracellular matrix in AAAs. Macrophages and T lymphocytes infiltrate the wall of AAAs, where they can produce cytotoxic mediators such as cytokines, perforin, and Fas/FasL. These death-promoting products of activated immune cells may contribute to elimination of SMCs, a source of elastin and collagen, during the pathogenesis of AAAs.
Key Words: aneurysm • muscle, smooth • cells • lymphocytes • apoptosis
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