The regulation of sympathetic outflow in chronic heart failure (CHF) is a complex process involving a variety of central and peripheral mediators. Angiotensin II (Ang II) in the central nervous system plays a pivotal role in determining the discharge sensitivity of neurons responsible for generating sympathetic outflow. Critical to the action of Ang II is the predominant receptor type, the ATi receptor (ATiR). Studies carried out in this project over the past 5 years have clearly shown an upregulation of ATiR expression at both the protein and message levels in various areas of the medulla and its role in increasing reactive oxidant species (ROS). Furthermore, we have shown an important modulation of ATiR expression and sympathetic nerve activity by exercise training (ExT) in the CHF state. In the current proposal we extend our investigation into the regulation of ATiR expression in the rostral ventrolateral medulla (RVLM). We now focus on transcriptional regulation of ATiR expression by two ubiquitous transcription factors. Activator Protein 1 (AP-1) and Nuclear Factor Kappa B (NFkB).
In Specific Aims 1 and 2 we propose that CHF modulates proteins necessary for the generation of AP-1 in the RVLM. These proteins include c-fos, c-jun and Jun N terminal Kinase (JNK). Furthermore, we will determine the role of NFkB and its inhibitor, IkB and its kinase (IkK) in activation of NFkB in CHF. We also provide evidence for activation of an additional transcription factor, Elk-1 which may be critical to ATiR regulation. The roles of ROS and ExT will be investigated in whole animal experiments as well as in neuronal cell cultures. In these experiments we will make use of chronic sympathetic nerve recordings in conscious animals and molecular suppression experiments using inhibitors and siRNA technology. The level of Ang II in the brain is dependent on its conversion from Ang I by Angiotensin Converting Enzyme (ACE) and its degradation to Ang (1-7) by ACE2. Therefore, in Specific Aims 3 and 4 we investigate the role of central ACE and overexpression of ACE2 on sympathetic nerve activity (SNA), baroreflex function and cardiac function in rats and mice with CHF. Based on our preliminary data we will investigate the effects of ExT on the central expression of ACE and ACE2. Using pharmacological inhibitors we will determine the role of ACE2 and Ang (1-7) on SNA in animals with CHF. In these two Specific Aims we will utilize viral tranfection of the RVLM and NTS in order to chronically over express ACE2. Furthermore, we will use a novel transgenic mouse model that over expresses human ACE2 selectively in neurons (syn- hACE2) to evaluate ACE2 on baroreflex function. SNA, ATiR and cardiac function in CHF.

Public Health Relevance

(See Instructions): Over 5 million people are afflicted with chronic heart failure in the United States. The sequelae of this disorder, such as sympatho-excitation, initiate a positive feedback loop that evokes further deterioration of cardiac function. It is critical to understand the neuronal mechanisms responsible for sympatho-excitation in CHF. Furthermore, this research will determine the mechanism that may be partly responsible for the therapeutic benefits of exercise training on sympathetic outflow in CHF. PROJECT/PERFORIVIANCE SITE(S) (if additional space is needed, use Project/Performance

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL062222-15
Application #
8509761
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
1999-07-05
Project End
2014-08-31
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
15
Fiscal Year
2013
Total Cost
$387,599
Indirect Cost
$126,591
Name
University of Nebraska Medical Center
Department
Type
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Zheng, Hong; Liu, Xuefei; Sharma, Neeru M et al. (2016) Urinary Proteolytic Activation of Renal Epithelial Na+ Channels in Chronic Heart Failure. Hypertension 67:197-205
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Patel, Kaushik P; Xu, Bo; Liu, Xuefei et al. (2016) Renal Denervation Improves Exaggerated Sympathoexcitation in Rats With Heart Failure: A Role for Neuronal Nitric Oxide Synthase in the Paraventricular Nucleus. Hypertension 68:175-84
Vaz, Gisele C; Sharma, Neeru M; Zheng, Hong et al. (2016) Liposome-entrapped GABA modulates the expression of nNOS in NG108-15 cells. J Neurosci Methods 273:55-63
Schiller, Alicia M; Pellegrino, Peter Ricci; Zucker, Irving H (2016) Eppur Si Muove: The dynamic nature of physiological control of renal blood flow by the renal sympathetic nerves. Auton Neurosci :
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Pügge, Carolin; Mediratta, Jai; Marcus, Noah J et al. (2016) Exercise training normalizes renal blood flow responses to acute hypoxia in experimental heart failure: role of the α1-adrenergic receptor. J Appl Physiol (1985) 120:334-43
Sharma, Neeru M; Cunningham, Craig J; Zheng, Hong et al. (2016) Hypoxia-Inducible Factor-1α Mediates Increased Sympathoexcitation via Glutamatergic N-Methyl-d-Aspartate Receptors in the Paraventricular Nucleus of Rats With Chronic Heart Failure. Circ Heart Fail 9:

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