© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Age-dependent increase in c-fos activity and cyclin A expression in vascular smooth muscle cells
A potential link between aging, smooth muscle cell proliferation and atherosclerosis
aDepartment of Medicine (Cardiology), St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135, USA
bUnit of Vascular Biology, Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Cientìficas, 46010-Valencia, Spain
* Corresponding author. Tel.: +96-33-91-752; fax: +96-36-90-800 vandres{at}ibv.csic.es
Objective: Aging can be defined as a progressive deterioration of biological functions after the organism has attained its maximal reproductive competence, which is usually associated with a decrease in proliferative ability in most cell types. However, in certain pathological situations such as atherosclerosis and restenosis, aging has been shown to be associated with a higher level of vascular smooth muscle cell (VSMC) proliferation and neointimal lesion formation after angioplasty. In the present study, we investigated potential mechanisms involved in the age-dependent increase in VSMC proliferation. Methods and results: Primary cultures of VSMCs were isolated from young (6–8-month-old) and old (4–5-year-old) New Zealand rabbits. Results from cell counting assays and FACS analysis were consistent with a shortening of the cell cycle in old VSMCs. Western blot analysis in serum stimulated cells showed a significant increase in the level of cyclin A and cyclin-dependent kinase 2 proteins in the old vs. young VSMCs. In marked contrast, expression of cyclin E in VSMCs was not influenced by aging. Transient transfection assays showed an age-dependent increase in transcription from the human cyclin A promoter. Parallel studies demonstrated that the expression of the AP1 transcription factor c-fos, which interacts with the cyclin A promoter and stimulates VSMC proliferation, was also increased in old VSMCs. Consistent with this notion, electrophoretic mobility shift assays demonstrated an increase in AP1 DNA-binding activity in old VSMCs. Conclusions: These studies suggest that age-associated increase in c-fos activity contributes to augmented cyclin A expression and VSMC proliferation in old animals. These mechanisms might contribute to the higher prevalence and severity of atherosclerosis in the elderly.
KEYWORDS Aging; Gene expression; Smooth muscle
1 Present address: Department of Medicine (Cardiology), Centre Hospitalier de l’Université de Montréal, Montréal, Québec, H2L 4M1 Canada.