Hypertension is characterized by a sustained increase in blood pressure and is a major risk factor for other cardiovascular diseases such as ischemic heart disease, cardiac remodeling, cardiac failure, peripheral vascular disease and progressive renal damage. In addition, hypertension is a major risk factor for both degenerative (Alzheimer's) and vascular dementias and is therefore of critical importance in aging. Both aging and hypertension are associated with an increased sympathetic drive. Dysfunction of the rostral ventrolateral medulla (RVLM), a presympathetic brain area contributes to the development of hypertension. In microarray experiments, we identified increased expression of apelin in the RVLM of spontaneously hypertensive rats, a genetic model of hypertension. Apelin is the recently identified endogenous ligand for the G-protein coupled angiotensin 1-like receptor (APJ). Previous studies have demonstrated that microinjections of the active apelin13 fragment into the RVLM results in an increase in blood pressure. Based on these studies and our preliminary data we hypothesized that increased expression of apelin in the RVLM contributes to the development of hypertension and related neural complications. The following specific aims are planned to investigate this hypothesis: 1) validate the concept that apelin expression is increased in the RVLM in hypertension with the use of other genetic models, 2) determine whether over-expression of apelin in the RVLM results in hypertension, and 3) determine whether phosphoinositide 3-kinase activation and reactive oxygen species (ROS) generation, mechanisms that act in the RVLM to mediate hypertension, result in the cellular effects of apelin. We will also assess whether these mechanisms are augmented in hypertension. We will employ state-of-the-art physiological genomic techniques such as viral vector-mediated gene transfer and high resolution magnetic resonance imaging in these studies. We believe that our proposed studies are highly innovative and novel in that they will delineate the mechanism of action of apelin, a unique peptide in the neural regulation of hypertension. In addition, hypertension and dementias share pathogenic mechanisms as both may result from ROS-mediated oxidative stress. Our studies therefore hold the potential for a mechanism based approach to hypertension therapy that would ameliorate oxidative stress within the brain and may thereby limit progression of dementia. Our investigative team coupled with the state-of-the-art facilities at the Mcknight Brain Institute puts us in a unique environment to undertake these studies. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS055008-01
Application #
7073883
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Jacobs, Tom P
Project Start
2006-04-19
Project End
2008-01-31
Budget Start
2006-04-19
Budget End
2007-01-31
Support Year
1
Fiscal Year
2006
Total Cost
$182,604
Indirect Cost
Name
University of Florida
Department
Physiology
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
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Yao, Fanrong; Modgil, Amit; Zhang, Qi et al. (2011) Pressor effect of apelin-13 in the rostral ventrolateral medulla: role of NAD(P)H oxidase-derived superoxide. J Pharmacol Exp Ther 336:372-80
Zhang, Qi; Yao, Fanrong; Raizada, Mohan K et al. (2009) Apelin gene transfer into the rostral ventrolateral medulla induces chronic blood pressure elevation in normotensive rats. Circ Res 104:1421-8