The prevalence of coronary artery disease increases with age, and age itself is an independent risk factor for atherogenesis. Increased susceptibility to cellular stress and accrual of damage to vascular tissues are likely factors in the atherogenic milieu attributable to aging, yet the precise molecular processes underlying the age-associated events culminating in 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 contribute to the atherogenic process. We have also begun to consider the general role of the cellular chaperone machinery in the cell stress response, particularly as these events may be relevant to atherosclerotic lesion formation. In particular, we have recently cloned and characterized a novel co-chaperone/ubiquitin ligase, CHIP (carboxyl terminus of Hsc70-interacting protein), and have identified a surprising central role for this protein in balancing protein folding and degradation and regulating the stress response through its ability to activate the crucial stress-regulatory transcription factor HSF1. As proof that CHIP has a central role in stress-responsive events relevant to vascular aging, we have generated mice deficient in CHIP that have an impaired stress response and many features that are consistent with accelerated aging. We will now begin to explore the molecular events that link these processes in the present proposal. To do this, we propose four aims:
Specific aim #1 -- Determine the effects of CHIP deficiency on aging-related phenotypes;
Specific aim #2 -- Establish the cellular consequences of CHIP deficiency in vascular smooth muscle cells in vitro;
Specific aim #3 -- Determine the role of the cell stress regulation on vascular phenotypes and atherogenesis in vivo;
Specific aim #4 --- Examine the interactions of the chaperone system with oxidative metabolism and IGF-1 signaling. These studies will create a portrait of the interactions between chaperone dysfunction, chronic oxidative injury, and alterations in IGF-1 signaling that determine the vascular response to 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 |
Showing the most recent 10 out of 25 publications
