Competition between the toxin and hypoxia inducible factor responsive (HIF) pathways for a common heterodimer partner Arnt/HIF1b has been demonstrated using in vitro assays and cell culture lines. Evidence is accumulating that these pathways act at critical stages of cardiovascular development including early development of the coronary vasculature. The toxin TCDD, the prototypical agonist for AhR (aryl hydrocarbon receptor) of the toxin pathway, causes abnormal development of the coronary vascular that precedes and may be the basis for TCDD-induced dilated cardiomyopathy. Our findings identify the outflow tract myocardium as the cardiac tissue with the lowest oxygen tension (most hypoxic) at stages and site coincident with cardiomyocyte apoptosis, VEGFR2 expression, nuclear localization of HIF-1a, and accumulation of endothelial precursors of the coronary vasculature. Furthermore, this hypoxia is critical for normal cardiac development. When simultaneously subjected to both stresses, low oxygen tension during normal development and toxin exposure, the molecular and cellular events at this stage and site may be particularly susceptible to competition for signaling molecules such as Arnt/HIF1b resulting in imbalanced gene expression and abnormal development. Our working hypothesis is that activation of the toxin pathway will interfere with normal HIF signaling and HIF-induced gene expression required for cardiogenesis. We will compare the expression of HIF responsive genes with and without TCDD exposure in normally hypoxic cardiac regions of the avian embryo. We will also specifically disrupt HIF signaling by interfering with HIF1a binding in cardiomyocytes in ovo by viral transfection and compare cardiac and coronary vascular phenotypes to that of TCDD-treated embryos. This analysis would be expected to uncover the mechanisms of normal cardiac and coronary vascular development as well as the etiology of cardiotoxicity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21ES013507-01
Application #
6855234
Study Section
Special Emphasis Panel (ZRG1-CDD (01))
Program Officer
Mastin, Patrick
Project Start
2005-09-09
Project End
2007-08-31
Budget Start
2005-09-09
Budget End
2006-08-31
Support Year
1
Fiscal Year
2005
Total Cost
$227,477
Indirect Cost
Name
Case Western Reserve University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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Karunamuni, Ganga; Yang, Ke; Doughman, Yong Qiu et al. (2010) Expression of lymphatic markers during avian and mouse cardiogenesis. Anat Rec (Hoboken) 293:259-70
Yang, Ke; Doughman, Yong-Qiu; Karunamuni, Ganga et al. (2009) Expression of active Notch1 in avian coronary development. Dev Dyn 238:162-70
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Wikenheiser, Jamie; Wolfram, Julie A; Gargesha, Madhusudhana et al. (2009) Altered hypoxia-inducible factor-1 alpha expression levels correlate with coronary vessel anomalies. Dev Dyn 238:2688-700
Penning, Trevor M; Lerman, Caryn (2008) Genomics of smoking exposure and cessation: lessons for cancer prevention and treatment. Cancer Prev Res (Phila Pa) 1:80-3