Environmental chemicals are significant risk factors for atherosclerotic vascular disease, but molecular mechanisms of atherogenesis have not been elucidated with certainty. Research in this laboratory during the previous funding cycle established that transcriptional deregulation of gene expression by aromatic hydrocarbons is a critical event in the induction of proliferative (i.e. atherogenic) phenotypes in vascular smooth muscle cells (vSMCs). Challenge with atherogenic hydrocarbons was shown to alter redox status and trigger a complex cellular response that culminates in modulation of vascular gene expression. Of particular relevance was the finding that functional interactions between aryl hydrocarbon receptor (AhR) and proteins that bind the antioxidant/electrophile response element (AREBpRE) are central to the loss of transcriptional control in hydrocarbon-treated cells. On the basis of these findings our unifying hypothesis is that deregulation of gene expression in vSMCs by aromatic hydrocarbons involves complex interactions between activated ARE/EpRE binding proteins, AhR, and co-regulators of transcription during the course of the atherogenic response. To test this hypothesis, experiments are proposed to purify and clone AREJEpRE binding proteins from vascular tissue following chemical injury, evaluate the role of HMG-1 (Y) as a co-regulator of ARFJEpRE-regulated gene transcription in vSMCs, and characterize promoter-specific patterns of trans-regulation in vSMCs. These studies will enable us to define the role of ARE/EpRE binding proteins in oxidant-induced atherogenesis and identify critical transacting factors involved in the atherogenic response to environmental injury.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Alcohol and Toxicology Subcommittee 4 (ALTX)
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Mastin, Patrick
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University of Louisville
Schools of Medicine
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Ramos, Kenneth S; Stribinskis, Vilius; Steffen, Marlene C et al. (2013) Albumin-like proteins are critical regulators of vascular redox signaling. Oxid Med Cell Longev 2013:628615
Montoya-Durango, Diego E; Ramos, Kenneth S (2012) HPV E7 viral oncoprotein disrupts transcriptional regulation of L1Md retrotransposon. FEBS Lett 586:102-6
Williams, E Spencer; Wilson, Emily; Ramos, Kenneth S (2012) NF-?B and matrix-dependent regulation of osteopontin promoter activity in allylamine-activated vascular smooth muscle cells. Oxid Med Cell Longev 2012:496540
Ramos, Kenneth S; Montoya-Durango, Diego E; Teneng, Ivo et al. (2011) Epigenetic control of embryonic renal cell differentiation by L1 retrotransposon. Birth Defects Res A Clin Mol Teratol 91:693-702
Nanez, Adrian; Ramos, Irma N; Ramos, Kenneth S (2011) A mutant Ahr allele protects the embryonic kidney from hydrocarbon-induced deficits in fetal programming. Environ Health Perspect 119:1745-53
Teneng, Ivo; Montoya-Durango, Diego E; Quertermous, James L et al. (2011) Reactivation of L1 retrotransposon by benzo(a)pyrene involves complex genetic and epigenetic regulation. Epigenetics 6:355-67
Montoya-Durango, D E; Ramos, K S (2010) L1 retrotransposon and retinoblastoma: molecular linkages between epigenetics and cancer. Curr Mol Med 10:511-21
Montoya-Durango, Diego E; Liu, Yongqing; Teneng, Ivo et al. (2009) Epigenetic control of mammalian LINE-1 retrotransposon by retinoblastoma proteins. Mutat Res 665:20-8
Ramos, Kenneth S (2009) H-RAS controls phenotypic profiles of vascular smooth muscle cells and the pathogenesis of vascular proliferative disorders. Circ Res 104:1139-41
Zhang, Yong; Ramos, Kenneth S (2008) The development of abdominal aortic aneurysms in mice is enhanced by benzo(a)pyrene. Vasc Health Risk Manag 4:1095-102

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