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Abstract

Grant Number:	5R21AT002739-02
Project Title:	Genistein and cAMP signaling in vascular endothelium

PI Information:	Name	Email	Title
	LIU, DONGMIN	doliu@vt.edu

Abstract: DESCRIPTION (provided by applicant): The long-range goal of this research is to develop novel vasoactive agents that may be of benefit in lowering the high level of cardiovascular morbidity in the aging American population. Recent studies have shown that ingestion of soy protein associated with isoflavones may have a protective role in vasculature. Genistein, the major soy isoflavone, has various biologgical actions. However, it is not clear whether the beneficial effect of soy protein is due to genistein or other components. In addition, the cellular or molecular mechanisms underlying the vessel protective effect of soy products remain unclear. We recently found that genistein directly acts on vascular dothelial cells (EC), leading to cAMP accumulation, nitric oxide synthase (eNOS) activation and expression. Further, We demonstrated that genistein induced a rapid decrease in systemic blood pressure (BP) in rats. The objective of this application, is therefore to determine how genistein triggers the cAMP signaling pathway and thereby influencing the cAMP-related vascular function. The four following questions will be addressed: 1). How does genistein elevate cAMP, activate eNOS, and consequently stimulate nitric oxide in EC? 2) Does genistein decrease BP in animals through activation of the cAMP signaling? 3). Does elevated cAMP by genistein also alter eNOS gene expression ? 4). Does genistein protect endothelial barrier function via the cAMP signaling? We will employ cellular, molecular and biochemical analysis to determine whether genistein elevates cAMP via activation of Gs-mediated adenylate cyclase in EC. Genistein-regulated eNOS gene expression will be evaluated by ribonuclease protection assay and Real-Time PCR. The effect of genistein on endothelial barrier function, as determined by cytoskeletal reorganization and barrier permeability, will be assessed using immunocytochemistry, confocal microscope and macromolecular leakage methods. Pharmacological and molecular intervention approaches will be used to detemine the involvement of a specific pathway in mediation of genistein action. The results from these studies will establish the mechanisms of the genistein action in vasculature and thereby provide foundation for further studies to determine the effects of genistein on vascular health and diseases such as hypertension. The demonstration of the health benefits of soy isoflavones in vasculature is expected to have significant effect on public health since isoflavones are widely used as a dietary supplements.

Public Health Relevance:
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Institution:	VIRGINIA POLYTECHNIC INST AND ST UNIV
	OFFICE OF SPONSORED PROGRAMS
	BLACKSBURG, VA 24060
Fiscal Year:	2008
Department:	HUMAN NUTRITION, FOODS, & EXERCISE
Project Start:	01-SEP-2007
Project End:	30-APR-2009
ICD:	NATIONAL CENTER FOR COMPLEMENTARY & ALTERNATIVE MEDICINE
IRG:	ZAT1

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