Aging, oxidative responses, and proliferative capacity in cultured mouse aortic smooth muscle cells

The cellular mechanisms that contribute to the acceleration of atherosclero sis in aging populations are poorly understood, although it is hypothesized that changes in the proliferative capacity of vascular smooth muscle cells is contributory. We addressed the relationship among aging, generation of reactive oxygen species (ROS), and proliferation in primary culture smooth muscle cells (SMC) derived from the aortas of young (4 mo old) and aged (16 mo old) mice to understand the phenotypic modulation of these cells as agi ng occurs. SMC from aged mice had decreased proliferative capacity in respo nse to alpha -thrombin stimulation, yet generated higher levels of ROS and had constitutively increased mitogen-activated protein kinase activity, in comparison with cells from younger mice. These effects may be explained by dysregulation of cell cycle-associated proteins such as cyclin D1 and p27Ki p1 in SMC from aged mice. Increased ROS generation was associated with decr eased endogenous antioxidant activity, increased lipid peroxidation, and mi tochondrial DNA damage. Accrual of oxidant-induced damage and decreased pro liferative capacity in SMC may explain, in part, the age-associated transit ion to plaque instability in humans with atherosclerosis.