The prevalence of coronary artery disease increases with age, and age itself is an independent risk factor for atherogenesis. Reactive oxygen species (ROS) and accrual of oxidative damage are likely factors in the atherogenic milieu attributable to aging, yet the molecular lesions in age- associated atherosclerotic lesion formation remain to be determined. Our recent data indicate that mice provide an excellent model for understanding the intrinsic effects of aging on vascular wall biology that may contribute to our understanding of the atherogenic process. In addition, we have been exploring the relationship between ROS generation, vascular cell phenotypes, and atherosclerotic lesion formation using in vitro and in vivo mouse models. Having established an association between aging, ROS production, and atherosclerotic lesion formation in SMCs, we will now begin to explore the molecular events that link these processes in the present proposal. To do this, we propose five aims:
Specific aim number 1- Quantify the impact of increased and decreased ROS production on the vascular phenotypes of aged atherosclerosis-prone mice on the ApoE (-/-) background;
Specific aim number 2- Examine the proliferative phenotypes and signaling pathways activated in aged SMCs with altered ROS metabolism using novel methods we have developed to isolate SMCs from mouse aortas. We will determine how altered ROS generation affects the development and progression of SMC signaling events and proliferative changes associated with aging;
Specific aim number 3- Determine the mechanism(s) whereby cell cycle entry is attenuated in SMCs from aged mice by exploring the molecular events that mediate the disparity in proliferation we have observed between SMCs obtained from young and old mice, with a focus on signaling and transcriptional events we know to participate in the proliferative response of SMCs;
Specific aim number 4- Establish whether changes in protective systems in addition to antioxidants contribute to vascular cell phenotypes of aged mice. In particular, we will examine the expression of molecular chaperones in mice of different backgrounds and ages, and we will determine how SMC aging and oxidative challenges are modified by regulators of molecular chaperones;
Specific aim number 5- Characterize the ROS-dependent and ROS-independent transcriptional profiles of SMCs from aged mice in comparison with gene expression patterns of SMCs deficient in their ability to metabolize ROS. Based on these studies, we will create molecular portraits of the ROS-dependent and ROS-independent transcripts preferentially associated with aging.
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