Heart failure is the most common reason for hospitalization in the United States among those older than 65 years, and this statistic is expected to grow as the population ages. Overactivity of the sympathetic nervous system is a cardinal manifestation of the heart failure syndrome, and a strong predictor of morbidity and mortality. The etiology of increased sympathetic activity in heart failure is multifactorial. Recent studies have implicated inflammatory mechanisms that generate reactive oxygen species, particularly activation of nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase dependent superoxide, in cardiovascular regions of the brain. The ability of angiotensin II to generate superoxide and sympathetic drive by this mechanism has been well studied - almost to the exclusion of other inflammatory mediators that are also increased in heart failure and might well contribute. The present project examines the potential role of the pro- inflammatory cytokines, which increase in plasma and brain of rats with ischemia-induced heart failure, are capable of NAD(P)H oxidase driven superoxide production, and are known to contribute to increased sympathetic drive in heart failure. We will test three hypotheses with regard to the mechanisms by which pro- inflammatory cytokines might activate the sympathetic nervous system in a rat model of ischemia-induced heart failure that mimics the most common form of heart failure in humans: 1) pro-inflammatory cytokines increase sympathetic nerve activity in heart failure rats by inducing cyclooxygenase-2 activity and the production of prostaglandin E2, which is sympatho-excitatory in the brain;2) pro-inflammatory cytokines increase sympathetic nerve activity in heart failure rats by upregulating the brain renin-angiotensin system and the production of angiotensin II, which is sympatho-excitatory in the brain in its own right as well as by stimulating superoxide production;and 3) pro-inflammatory cytokines directly stimulate NAD(P)H oxidase dependent superoxide production. This project focuses upon the actions of pro-inflammatory cytokines in the paraventricular nucleus of the hypothalamus, a forebrain cardiovascular regulatory center that has been identified as an important source of the increased sympathetic nerve activity in heart failure. Neurochemical changes in the paraventricular nucleus in heart failure, and the cellular and molecular mechanisms which regulate them, will be investigated using molecular and immunohistochemical/immunofluorescent methods, and the results of those studies will be correlated with functional data from electrophysiological studies examining the effects of manipulating key putative mediators of sympathetic nerve activity. These studies will identify currently unrecognized mechanisms driving the sympathetic nervous system in heart failure, and thus potential targets for preventive intervention.

Public Health Relevance

New approaches are needed to treat heart failure, which remains a devastating disorder despite current therapy. One aspect of heart failure that is not treated and is still poorly understood is the inflammatory response, manifest primarily by an increase in circulating pro-inflammatory cytokines. This project seeks to determine how inflammation contributes to activation of the sympathetic nervous system - a marker of adverse outcome in heart failure - and to discover novel ways of reducing its impact.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL073986-09
Application #
8389884
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Wang, Lan-Hsiang
Project Start
2003-07-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2014-11-30
Support Year
9
Fiscal Year
2013
Total Cost
$353,430
Indirect Cost
$117,810
Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Wei, Shun-Guang; Zhang, Zhi-Hua; Beltz, Terry G et al. (2013) Subfornical organ mediates sympathetic and hemodynamic responses to blood-borne proinflammatory cytokines. Hypertension 62:118-25
Yu, Yang; Xue, Bao-Jian; Zhang, Zhi-Hua et al. (2013) Early interference with p44/42 mitogen-activated protein kinase signaling in hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension. Hypertension 61:842-9
Yu, Yang; Zhang, Zhi-Hua; Wei, Shun-Guang et al. (2012) Peroxisome proliferator-activated receptor-? regulates inflammation and renin-angiotensin system activity in the hypothalamic paraventricular nucleus and ameliorates peripheral manifestations of heart failure. Hypertension 59:477-84
Gudmundsson, Hjalti; Curran, Jerry; Kashef, Farshid et al. (2012) Differential regulation of EHD3 in human and mammalian heart failure. J Mol Cell Cardiol 52:1183-90
Zhang, Zhi-Hua; Yu, Yang; Wei, Shun-Guang et al. (2012) Aldosterone-induced brain MAPK signaling and sympathetic excitation are angiotensin II type-1 receptor dependent. Am J Physiol Heart Circ Physiol 302:H742-51
Wei, Shun-Guang; Zhang, Zhi-Hua; Yu, Yang et al. (2012) Central actions of the chemokine stromal cell-derived factor 1 contribute to neurohumoral excitation in heart failure rats. Hypertension 59:991-8
Zhang, Zhi-Hua; Yu, Yang; Wei, Shun-Guang et al. (2011) EPýýý receptors mediate PGEýýý-induced hypothalamic paraventricular nucleus excitation and sympathetic activation. Am J Physiol Heart Circ Physiol 301:H1559-69
Yu, Yang; Zhang, Zhi-Hua; Wei, Shun-Guang et al. (2010) Brain perivascular macrophages and the sympathetic response to inflammation in rats after myocardial infarction. Hypertension 55:652-9
Felder, Robert B (2010) Mineralocorticoid receptors, inflammation and sympathetic drive in a rat model of systolic heart failure. Exp Physiol 95:19-25
Zhang, Zhi-Hua; Yu, Yang; Wei, Shun-Guang et al. (2010) Centrally administered lipopolysaccharide elicits sympathetic excitation via NAD(P)H oxidase-dependent mitogen-activated protein kinase signaling. J Hypertens 28:806-16

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