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1 Program in Molecular Cardiology and 2 Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599-7075; and 3 Division of Cardiology and Sealy Center for Molecular Cardiology and 4 Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, Texas 77555
The cellular mechanisms that
contribute to the acceleration of atherosclerosis 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 aging occurs. SMC from aged mice had decreased proliferative capacity in response to 
-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 p27Kip1 in SMC from
aged mice. Increased ROS generation was associated with decreased endogenous antioxidant activity, increased lipid peroxidation, and
mitochondrial DNA damage. Accrual of oxidant-induced damage and
decreased proliferative capacity in SMC may explain, in part, the
age-associated transition to plaque instability in humans with atherosclerosis.
atherosclerosis; reactive oxygen species; cell cycle; DNA damage; lipid peroxidation
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