In patients with heart failure, the presence of circulating pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-a) and interleukin-1 beta (IL-lb) correlates directly with the severity of the disease and predicts a poor prognosis. The pro-inflammatory cytokines have been shown to activate the hypothalamicpituitary- adrenal (HPA) axis and stimulate the sympathetic nervous system. Corticotropin-releasing factor (CRF) in the paraventdcular nucleus of the hypothalamus (PVN) is the principal mediator of the humoral limb of this response (i.e., cortisol release); the mediator of the sympathetic limb is not known. Cytokine activation of the HPA axis is indirect: TNF-a and IL-lb stimulate receptors on the vascular endothelium to release prostaglandins E2 (PGE2), which crosses blood brain barrier to excite the norepinephrine (NE) containing neurons in rostral ventrolateral medulla that ascend to stimulate CRF production in PVN. This model has been derived from acute studies in normal rats. The overall hypothesis of this project is that chronic stimulation by pro-inflammatory cytokines contributes to the augmented sympathetic drive in heart failure. We will seek to determine: 1) which neurotransmitter substances (leading candidates being CRF, NE, PGE2) stimulate parvocellular PVN neurons that descend to activate centers of sympathetic drive in brain stem - leading candidates are CRF itself, exciting CRF-R1 receptors that are upregulated in PVN by stress, NE, which can excite PVN neurons via an alpha-1 adrenergic mechanism, and PGE2, which we have recently shown to elicit a response similar to blood-borne TNF-a when injected directly into PVN; 2) whether these presympathetic parvocellular PVN neurons are activated in heart failure over the classical pathway for acute cytokine stimulation of the HPA axis, described above, or by alternate mechanisms such as the local hypothalamic production of cytokines that we have recently observed in our ischemic heart failure model; in the latter case, presence of pro-inflammatory cytokines within the PVN might drive local production of PGE2 and CRF and release of NE from nerve terminals. These studies will be undertaken in a model of chronic ischemia-induced heart failure in rats, using electrophysiological, immunohistochemical and molecular techniques. These studies will provide new insights into the role of the pro-imflammatory cytokines in heart failure, perhaps leading to new therapeutic strategies.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiovascular and Renal Study Section (CVB)
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Massicot-Fisher, Judith
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University of Iowa
Internal Medicine/Medicine
Schools of Medicine
Iowa City
United States
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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
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
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
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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