Published online before print June 22, 2006, doi: 10.1161/01.RES.0000233315.38086.bc
© 2006 American Heart Association, Inc.
Molecular Medicine |
Vascular Smooth Muscle Cells Undergo Telomere-Based Senescence in Human Atherosclerosis
Effects of Telomerase and Oxidative Stress
From the Division of Cardiovascular Medicine (C.M., I.G., S.S., N.F., M.B.) and Department of Surgery (P.K.), University of Cambridge, Addenbrooke’s Hospital; and the Department of Surgery (A.R.) and Histopathology (M.G.), Papworth Hospital, Cambridge, UK.
Correspondence to Martin Bennett, Division of Cardiovascular Medicine Box 110, ACCI, Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK. E-mail mrb{at}mole.bio.cam.ac.uk
Although human atherosclerosis is associated with aging, direct evidence of cellular senescence and the mechanism of senescence in vascular smooth muscle cells (VSMCs) in atherosclerotic plaques is lacking. We examined normal vessels and plaques by histochemistry, Southern blotting, and fluorescence in situ hybridization for telomere signals. VSMCs in fibrous caps expressed markers of senescence (senescence-associated ß-galactosidase [SAßG] and the cyclin-dependent kinase inhibitors [cdkis] p16 and p21) not seen in normal vessels. In matched samples from the same individual, plaques demonstrated markedly shorter telomeres than normal vessels. Fibrous cap VSMCs exhibited markedly shorter telomeres compared with normal medial VSMCs. Telomere shortening was closely associated with increasing severity of atherosclerosis. In vitro, plaque VSMCs demonstrated morphological features of senescence, increased SAßG expression, reduced proliferation, and premature senescence. VSMC senescence was mediated by changes in cyclins D/E, p16, p21, and pRB, and plaque VSMCs could reenter the cell cycle by hyperphosphorylating pRB. Both plaque and normal VSMCs expressed low levels of telomerase. However, telomerase expression alone rescued plaque VSMC senescence despite short telomeres, normalizing the cdki/pRB changes. In vivo, plaque VSMCs exhibited oxidative DNA damage, suggesting that telomere damage may be induced by oxidant stress. Furthermore, oxidants induced premature senescence in vitro, with accelerated telomere shortening and reduced telomerase activity. We conclude that human atherosclerosis is characterized by senescence of VSMCs, accelerated by oxidative stress-induced DNA damage, inhibition of telomerase and marked telomere shortening. Prevention of cellular senescence may be a novel therapeutic target in atherosclerosis.
Key Words: atherosclerosis • smooth muscle • aging
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