Patients with heart failure (HF) and all animal models of HF exhibit an increased sympathetic neural activation, which increases the risk of morbidity and mortality. Standard therapy is to attempt to contain this sympatho- excitation in the face of reduced cardiac output. We have previously observed that neuronal activation within the paraventricular nucleus (PVN) of the hypothalamus may contribute to this elevated neuro-humoral drive. The mechanisms and source of this activation remain to be clearly delineated. Recently we uncovered enhanced excitatory mechanism mediated by 1) an intra-PVN hypoxia-induceable factor (HIF1-?); HIF1-? protein expression and immunostaining are increased in the PVN of rats with HF. A HIF1-? shRNA administered to the PVN normalized the increased renal sympathetic nerve activity (RSNA) in rats with HF. 2) A renal nerve dependent mechanism: Renal denervation (RDN) is a potentially new effective therapy for reducing sympathetic outflow in patients with hypertension. Our preliminary data shows that RDN reduces norepinephrine (NE) excretion in rats with HF, but not in sham rats, suggesting that RDN reduces sympatho- excitation in HF. Finally, as a therapeutic modality we have shown that exercise training (ExT) restores nNOS in the PVN and decreases neurohumoral activation in HF. This proposal tests the hypothesis that activation of HIF1-? and/or ascending information from the renal nerves contributes to the increased sympathetic drive in HF. Furthermore, ExT, may normalizes levels of HIF1-? and/or renal afferent input to the PVN in HF We propose to determine the underlying mechanisms for the activation of HIF1-? and/or ascending information from the renal nerves at the level of the PVN and subsequent sympatho-excitation in rats with HF. This goal will be accomplished by utilizing a multidisciplinary approach, ranging from studies in intact whole animals to studies in brain nuclei to individual neurons. We will use a variety of complementary techniques involving neuroanatomical, immunohistochemical, electrophysiological, molecular, cellular, and Adeno/Lenti viral gene transfer technology. The results will provide significant new information regarding central mechanisms of sympatho-excitation, specifically involvement of HIF1-? and/or ascending information from the renal nerves to the PVN in the increased sympathetic neural activation in the HF state. Understanding the role of these central mechanisms, not studied to date, in the increased sympathetic neural drive will enhance our ability to treat the HF condition and its cardiovascular complications.

Public Health Relevance

A hallmark of chronic heart failure (HF) is increased sympathetic drive. This abnormality increases the risk of morbidity and mortality during HF. While there has been some progress in elucidating the peripheral mechanisms involved in these abnormalities, the mechanisms thus far identified do not totally account for the elevated neuro-humoral drive during HF. Understanding the role of central mechanisms and the therapeutic value of RDN and exercise training will enhance our ability to treat the HF condition and its systemic complications. To date there is growing evidence that exercise training is beneficial however the central mechanisms involved remain to be elucidated.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL062222-18
Application #
9315896
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Tjurmina, Olga A
Project Start
Project End
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
18
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Nebraska Medical Center
Department
Type
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
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