The goal of our proposal, """"""""Oxidative Stress and Vascular Aging"""""""" (Project 1), is to investigate the interaction between aging and reactive oxygen species (ROS) in atherogenesis. It is well known that the prevalence of coronary artery disease increases with age, and that age itself is an independent risk factor for atherogenesis. However, specific molecular events in aging that are conducive to atherosclerotic lesion formation remain to be elucidated. We hypothesize that factors that alter ROS production in smooth muscle cells (SMCs) cause cellular and vascular dysfunction in both aging and atherosclerosis. The proposal is divided into four aims that synergistically integrate with Projects 2 and 3 and the Cores described in this application. These studies will utilize a number of experimental mouse models. Based on data from our group and others, mice provide an excellent model for understanding the intrinsic effects of aging on vascular wall biology that contribute to the atherogenic process. In addition, the relationships between ROS generation, vascular cell phenotypes, and atherosclerotic lesion formation are well suited for study using in vitro and in vivo mouse models. Having previously established an association between aging, ROS production, and atherosclerotic lesion formation, we will now begin to explore the molecular events that link these processes in the present proposal.
In specific aim 1, we will quantify the impact of increased and decreased ROS production on the vascular phenotypes of aged mice. The second specific aim describes experiments in which we will characterize the proliferative phenotypes and signaling pathways activated in aged SMCs with altered ROS metabolism. Given our prior demonstration that cell cycle entry is attenuated in SMCs from aged mice (even though these cells produce increased ROS), we will explore the molecular events that mediate this disparity, with a focus on signaling and transcriptional events in specific aim 3. Finally, in the fourth specific aim we will characterize the ROS-dependent and ROS-independent transcriptional profiles of SMCs from aged mice. We believe that these experiments, in the context of this Program Project Application, will allow us to identify the specific ROS-dependent and ROS-independent intracellular signals and transcriptional pattems that underlie long-term, age-related changes in SMC phenotype and, further facilitate the development of strategies to limit the atherosclerotic burden associated with aging.
| Lozhkin, Andrey; Vendrov, Aleksandr E; Pan, Hua et al. (2017) NADPH oxidase 4 regulates vascular inflammation in aging and atherosclerosis. J Mol Cell Cardiol 102:10-21 |
| Sun, Qi-An; Runge, Marschall S; Madamanchi, Nageswara R (2016) Oxidative stress, NADPH oxidases, and arteries. Hamostaseologie 36:77-88 |
| Vendrov, Aleksandr E; Vendrov, Kimberly C; Smith, Alberto et al. (2015) NOX4 NADPH Oxidase-Dependent Mitochondrial Oxidative Stress in Aging-Associated Cardiovascular Disease. Antioxid Redox Signal 23:1389-409 |
| Madamanchi, Nageswara R; Runge, Marschall S (2013) Redox signaling in cardiovascular health and disease. Free Radic Biol Med 61:473-501 |
| Zhou, Rui-Hai; Vendrov, Aleksandr E; Tchivilev, Igor et al. (2012) Mitochondrial oxidative stress in aortic stiffening with age: the role of smooth muscle cell function. Arterioscler Thromb Vasc Biol 32:745-55 |
| Ren, Hong Yu; Patterson, Cam; Cyr, Douglas M et al. (2011) Reconstitution of CHIP E3 ubiquitin ligase activity. Methods Mol Biol 787:93-103 |
| Aitsebaomo, Julius; Srivastava, Siddharth; Zhang, Hua et al. (2011) Recombinant human interleukin-11 treatment enhances collateral vessel growth after femoral artery ligation. Arterioscler Thromb Vasc Biol 31:306-12 |
| Ronnebaum, Sarah M; Patterson, Cam (2010) The FoxO family in cardiac function and dysfunction. Annu Rev Physiol 72:81-94 |
| Madamanchi, Nageswara R; Runge, Marschall S (2010) NADPH oxidases and atherosclerosis: unraveling the details. Am J Physiol Heart Circ Physiol 298:H1-2 |
| Runge, Marschall S; Molnar, Kimberly; Madamanchi, Nageswara R (2010) ""Old"" hearts and arteries: the role of oxidative stress. Trans Am Clin Climatol Assoc 121:52-8; discussion 59-60 |
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