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 #
5R01HL073986-08
Application #
8197258
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Wang, Lan-Hsiang
Project Start
2003-07-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
8
Fiscal Year
2012
Total Cost
$371,250
Indirect Cost
$123,750
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
Yu, Yang; Wei, Shun-Guang; Zhang, Zhi-Hua et al. (2016) ERK1/2 MAPK signaling in hypothalamic paraventricular nucleus contributes to sympathetic excitation in rats with heart failure after myocardial infarction. Am J Physiol Heart Circ Physiol 310:H732-9
Wei, Shun-Guang; Yu, Yang; Weiss, Robert M et al. (2016) Inhibition of Brain Mitogen-Activated Protein Kinase Signaling Reduces Central Endoplasmic Reticulum Stress and Inflammation and Sympathetic Nerve Activity in Heart Failure Rats. Hypertension 67:229-36
Xue, Baojian; Yu, Yang; Zhang, Zhongming et al. (2016) Leptin Mediates High-Fat Diet Sensitization of Angiotensin II-Elicited Hypertension by Upregulating the Brain Renin-Angiotensin System and Inflammation. Hypertension 67:970-6
Xue, Baojian; Thunhorst, Robert L; Yu, Yang et al. (2016) Central Renin-Angiotensin System Activation and Inflammation Induced by High-Fat Diet Sensitize Angiotensin II-Elicited Hypertension. Hypertension 67:163-70
Yu, Yang; Xue, Bao-Jian; Wei, Shun-Guang et al. (2015) Activation of central PPAR-γ attenuates angiotensin II-induced hypertension. Hypertension 66:403-11
Wei, Shun-Guang; Yu, Yang; Zhang, Zhi-Hua et al. (2015) Proinflammatory cytokines upregulate sympathoexcitatory mechanisms in the subfornical organ of the rat. Hypertension 65:1126-33
Wei, Shun-Guang; Zhang, Zhi-Hua; Yu, Yang et al. (2014) Central SDF-1/CXCL12 expression and its cardiovascular and sympathetic effects: the role of angiotensin II, TNF-α, and MAP kinase signaling. Am J Physiol Heart Circ Physiol 307:H1643-54
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
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
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

Showing the most recent 10 out of 28 publications