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Elucidating the Transcriptional Regulatory Network Underlying the Nts Response to Acute Hypertension

Gregory M. Miller1, Rajanikanth Vadigepalli2, James S. Schwaber2, and Babatunde A. Ogunnaike1. (1) Chemical Engineering, University of Delaware, 150 Academy St., Newark, DE 19716, (2) Daniel Baugh Institute for Functional Genomics and Computational Biology, Thomas Jefferson University, 1020 Locust St Room 575, Philadelphia, PA 19107

Hypertension, which affects one in three American adults, can lead to heart disease and stroke (NHLBI, 2008). Individuals with hypertension experience sustained elevated blood pressure because their blood pressure controllers appear to have adapted to a blood pressure set-point higher than that in normotensive individuals, suggesting a critical role for the blood pressure control system in the development and maintenance of hypertension. A major part of this control system is the nucleus tractus solitarius (NTS) in the brain, and NTS function has been shown to be compromised in hypertensive individuals, reflecting differences in NTS neurons between normotensive and hypertensive individuals. To treat hypertension effectively, we must understand the process by which NTS neurons adapt from the healthy state to the hypertensive state. Our overall objective, therefore, is to understand how neurons in the NTS change their cellular state to adapt from the healthy state to the hypertensive state.

To gain insight into how NTS cells are remodeled during the adaptation to the hypertensive state, we subject healthy animals to acute hypertension and then measure the response of their NTS cells at the level of gene and protein activity. Because NTS cells removed from animals subjected to this elevated blood pressure treatment have been found to exhibit a broad, dynamic gene expression response, gene expression is suspected to play a major role in this cellular adaptation (Khan et al, 2008). In this work, we identify the regulatory events orchestrating the gene expression response measured by Khan et al. Because the dominant mechanism by which changes in gene expression occur is through binding of transcription factors to their target gene promoters, we have focused on the network of transcription factors producing the gene expression response in the adaptation of NTS cells to the hypertensive state.

Because genes with AP-1 and CREB binding sites have been found to be significantly differentially expressed in the NTS from animals subjected to elevated blood pressure (Khan et al, 2008), we suspect that AP-1 and CREB are key transcription factors in the adaptation of NTS cells to the hypertensive state. To test this hypothesis, we perform chromatin immunoprecipitation experiments to measure AP-1 and CREB binding to the promoter regions of genes predicted to be regulatory targets of these transcription factors. Our experimental results show AP-1 and CREB bind differentially to genes known to be important for neuronal function in the NTS from animals with elevated blood pressure. These results support the role of AP-1 and CREB in central blood pressure regulation, and may lead to the identification of new pharmaceutical targets for hypertension.

References

Khan R.L. et al. (2008), Dynamic Transcriptomic Response to Acute Hypertension in the Nucleus Tractus Solitarius. Am. J. Physiol. Regul. Integr. Comp. Physiol.

National Heart Lung and Blood Institute Website, High Blood Pressure (2008). http://www.nhlbi.nih.gov/health/dci/Diseases/Hbp/HBP_WhatIs.html