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

• Published in: Cardiovascular research 2000-03, Vol.45 (4), p.1026-1034
• Main Authors: RIVARD, A, PRINCIPE, N, ANDRES, V
• Format: Article
• Language: English
• Subjects: Aging - metabolism; Animals; Arteriosclerosis - metabolism; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Blotting, Western; Cardiology. Vascular system; Cell Division - genetics; Cells, Cultured; Cyclin A - metabolism; Electrophoresis, Polyacrylamide Gel; Flow Cytometry; Gene Expression; Humans; Male; Medical sciences; Muscle, Smooth, Vascular - chemistry; Muscle, Smooth, Vascular - metabolism; Proto-Oncogene Proteins c-fos - metabolism; Rabbits; Transcription Factor AP-1 - metabolism
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1016/s0008-6363(99)00385-5

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. 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. 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.