Systolic heart failure (HF) is a devastating condition with high socioeconomic impact. Progress in the development of new pharmacological agents to treat HF is stagnant. Standard therapy targets the untoward peripheral effects of the heightened activity of the renin-angiotensin- system (RAS) and sympathetic nervous system (SNS), compensatory mechanisms that seek to maintain pressure in the face of a low cardiac output. As yet, there is no specific therapy for the inflammatory state that accompanies HF and contributes to adverse outcomes. Large clinical trials demonstrated no benefit of anti-cytokine agents, which can have serious side effects. Recent studies have revealed that the central nervous system actions of pro-inflammatory cytokines (PICs) contribute to the pathogenesis of HF - in particular, to the detrimental increase in sympathetic nerve activity. That work has focused almost exclusively on the effects of PICs inside the blood-brain barrier (BBB), with little attention to the effects of circulating PICs that reflect the peripheral inflammatory state but are too large to cross the BBB. Our preliminary studies demonstrate that blood-borne PICs act upon the subfornical organ (SFO), a forebrain circumventricular organ that lacks a BBB, to increase sympathetic activity in normal rats. We hypothesize that the high circulating levels of PICs in HF induce an inflammatory/excitatory state in the SFO that drives inflammatory/excitatory mechanisms downstream in the hypothalamic paraventricular nucleus (PVN) to increase peripheral sympathetic nerve activity. Since PIC receptors mediate molecular rather than synaptic events, their effects on the SFO are likely mediated by upregulation of intracellular signaling mechanisms related to RAS, reactive oxygen species, and endoplasmic reticulum stress. The proposed studies will: 1) determine the contribution of tumor necrosis factor (TNF)-a and interleukin (IL)-1b, acting upon their receptors in SFO, to sympathetic excitation in normal rat and rats with HF;2) identify the cellular and molecular mechanisms activated in the SFO by TNF-a and IL-1b, and their impact on cellular and molecular mechanisms downstream in PVN;3) determine whether counteracting the effects of PICs at the SFO level is a viable potential therapeutic strategy to reduce sympathetic excitation and its consequences in HF. A combination of molecular, immunohistochemical, and in vivo electrophysiological and hemodynamic recording techniques will be used to elucidate the mechanisms by which blood-borne PICs, acting on the SFO, influence neurohumoral excitation. Since the SFO lacks a BBB, these studies may identify targets for therapeutic intervention in the inflammatory process in HF that are accessible to systemic drug administration.

Public Health Relevance

This project will determine the mechanisms by which blood-borne pro-inflammatory cytokines, acting on the subfornical organ (SFO) in the forebrain, contribute to activation of the sympathetic nervous system in a rat model of systolic heart failure By learning more about molecular mechanisms in SFO that respond to peripheral inflammation, we hope to identify targets for the treatment of central mechanisms driving sympathetic activity in heart failure. As a circumventricular organ lacking a blood-brain barrier, the SFO is accessible to systemically administered drugs that may counter the central inflammatory response.

National Institute of Health (NIH)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Wang, Lan-Hsiang
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University of Iowa
Internal Medicine/Medicine
Schools of Medicine
Iowa City
United States
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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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