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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL073986-10A1
Application #
8758110
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wang, Lan-Hsiang
Project Start
2003-07-01
Project End
2018-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Yu, Yang; Wei, Shun-Guang; Weiss, Robert M et al. (2018) Angiotensin II Type 1a Receptors in the Subfornical Organ Modulate Neuroinflammation in the Hypothalamic Paraventricular Nucleus in Heart Failure Rats. Neuroscience 381:46-58
Yu, Yang; Wei, Shun-Guang; Weiss, Robert M et al. (2018) Sex Differences in the Central and Peripheral Manifestations of Ischemia-induced Heart Failure in Rats. Am J Physiol Heart Circ Physiol :
Wei, Shun-Guang; Yu, Yang; Felder, Robert B (2018) Blood-borne interleukin-1? acts on the subfornical organ to upregulate the sympathoexcitatory milieu of the hypothalamic paraventricular nucleus. Am J Physiol Regul Integr Comp Physiol 314:R447-R458
Yu, Yang; Wei, Shun-Guang; Weiss, Robert M et al. (2017) TNF-? receptor 1 knockdown in the subfornical organ ameliorates sympathetic excitation and cardiac hemodynamics in heart failure rats. Am J Physiol Heart Circ Physiol 313:H744-H756
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
Wei, Shun-Guang; Yu, Yang; Weiss, Robert M et al. (2016) Endoplasmic reticulum stress increases brain MAPK signaling, inflammation and renin-angiotensin system activity and sympathetic nerve activity in heart failure. Am J Physiol Heart Circ Physiol 311:H871-H880
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
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
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
Yu, Yang; Xue, Bao-Jian; Wei, Shun-Guang et al. (2015) Activation of central PPAR-? attenuates angiotensin II-induced hypertension. Hypertension 66:403-11

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