Professor
Specialty: Pharmacology & Toxicology
Division of Pharmaceutical
Sciences
Office: Research Incubator Building, room 293
Phone: 505.272.0580
My laboratory studies the function of the aryl hydrocarbon receptor (AhR) in cardiovascular development and physiology. The AhR is an orphan receptor that belongs to the basic-helix-loop-helix-PAS superfamily of transcription factors. Although an endogenous ligand for the AhR has not been identified, environmental pollutants, such as the halogenated aromatic hydrocarbons (like dioxin), represent high affinity ligands for the AhR. It is most notable that both (a) sustained activation of AhR by these pollutants and (b) genetic deletion of the AhR result in cardiovascular disease, suggesting that the AhR functions to maintain physiological balance of the cardiovascular system, such that either excessive or insufficient receptor activation disrupts this homeostasis. We use mice exposed to dioxin or mice lacking AhR expression to elucidate the role of the AhR in cardiovascular homeostasis.
Specifically, we study: (1) the mechanisms by which high affinity ligands for the AhR, typified by the environmental pollutant dioxin increase the incidence and pathological severity of cardiovascular disease, including from early fetal exposures as well as adult exposures; and (2) the mechanisms underlying cardiovascular disease, including cardiac hypertrophy, hypertension, and cardiac dysfunction, in an AhR knockout mouse model and an endothelial cell-specific AhR knockout mouse model.
Lund, A.K., M.B. Goens, N.L. Kanagy, and M.K. Walker. 2003. Cardiac hypertrophy in aryl hydrocarbon null (AhR) null mice is correlated with elevated angiotensin II, endothelin-1 and mean arterial blood pressure. Toxicol. Appl. Pharmacol.,193, 177-187.
Ivnitski-Steele, I.D., A. Sanchez, and M.K. Walker. 2004. 2,3,7,8-Tetrachlorodibenzo-p-dioxin reduces myocardial hypoxia and vascular endothelial growth factor expression during chick embryo development. Birth Defects Research: Clin. Mol.Teratol.,70, 51-58.
C.D. Johnson, Y. Balagurunathan, M.G. Tadesse, M.H. Falahatpisheh, M.K. Walker, E.R. Dougherty, K.S. Ramos. 2004. Unraveling gene-gene interactions regulated by ligands of the aryl hydrocarbon receptor. EHP Toxicogenomics, 112, 403-412.
Berwick, M., G. Matullo, Y.S. Song, S. Guarrera, G. Dominguez, I. Orlow, M.K. Walker, P. Vineis. 2004. Association between AhR genotype and survival in soft tissue sarcoma. J. Clin. Oncol., 22, 3997-4001.
Ivnitski-Steele, I.D., M. Chavez, M. Friggens, and M.K. Walker. 2005. 2,3,7,8-Tetrachlorodibenzo-p-dioxin inhibits coronary vasculogenesis, in part, by reduced endothelial cell responsiveness to angiogenic stimuli, including vascular endothelial growth factor-A. Birth Defects Research: Clin. Mol. Teratol.,73, 440-446.
Lund, A.K., S. Peterson, G. Timmins, and M.K. Walker. 2005. Endothelin-1-mediated increase in reactive oxygen species and NADPH oxidase activity in heart of aryl hydrocarbon receptor null mice. Toxicol. Sci., 88, 265-273.
Thackaberry, E.A., Jiang, Z., Johnson, C.D., K.S. Ramos, and M.K. Walker. 2005. Toxicogenomic profile of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the fetal murine heart: Modulation of cell cycle and extracellular matrix genes. Toxicol. Sci, 88, 231-241.
Thackaberry, E.A., B.A. Nunez, I.D. Ivnitski-Steele, M. Friggens, and M.K. Walker. 2005. Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on murine heart development: Alteration in fetal and postnatal cardiac growth, and postnatal cardiac chronotropy. Toxicol. Sci, 88, 242-249.
Lund, A.K., M.B. Goens, B.A. Nunez, M.K. Walker. 2006. Characterizing the role of endothelin-1 in the progression of cardiac hypertrophy in aryl hydrocarbon receptor null mice. Toxicol. Appl. Pharmacol., 212, 127-135.
Zhang, N. and M.K. Walker. 2007. Crosstalk between the aryl
hydrocarbon receptor and hypoxia on the constitutive expression of
cytochrome P4501A1 mRNA. Cardiovas. Toxicol. 7, 282-290
Aragon, A.C., P.G. Kopf, J.K. Huwe, E.J. Bedrick, and M.K. Walker. 2008.
In utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure:
I. Effects on fetal and adult cardiac gene expression. Toxicol. Sci.
101, 321-330
Lund, A.K., L.N. Agbor, N. Zhang, A. Baker, H. Zhao, G.D. Fink, N.L.
Kanagy, and M.K. Walker. 2008. Loss of the aryl hydrocarbon receptor
induces hypoxemia, endothelin-1, and systemic hypertension at modest
altitude. Hypertension. 51, 803-809.
de Frutos, S., L. Duling, D. Alo, T. Berry, O. Jackson-Weaver, M.K.
Walker, N.L. Kanagy, and L.V. Gonzalez Bosc. 2008. NFATc3 is required
for intermittent hypoxia-induced hypertension. Am J Physiol Heart Circ
Physiol. Mar 21; [Epub ahead of print] PMID: 18359899
The
University of New Mexico’s Doctor of Pharmacy program is
accredited by the Accreditation Council for Pharmacy Education,
20 North Clark Street, Suite 2500, Chicago, IL 60602-5109, TEL
(312) 664-3575 , FAX (312) 664-4652,
URL
http://www.acpe-accredit.org/
05/07/2008 11:52:35 AM -0600.