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

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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University of Nebraska Medical Center
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Haack, Karla K V; Zucker, Irving H (2015) Central mechanisms for exercise training-induced reduction in sympatho-excitation in chronic heart failure. Auton Neurosci 188:44-50
Wang, Han-Jun; Wang, Wei; Cornish, Kurtis G et al. (2014) Cardiac sympathetic afferent denervation attenuates cardiac remodeling and improves cardiovascular dysfunction in rats with heart failure. Hypertension 64:745-55
Zucker, Irving H; Xiao, Liang; Haack, Karla K V (2014) The central renin-angiotensin system and sympathetic nerve activity in chronic heart failure. Clin Sci (Lond) 126:695-706
Haack, Karla K V; Marcus, Noah J; Del Rio, Rodrigo et al. (2014) Simvastatin treatment attenuates increased respiratory variability and apnea/hypopnea index in rats with chronic heart failure. Hypertension 63:1041-9
Marcus, Noah J; Del Rio, Rodrigo; Schultz, Evan P et al. (2014) Carotid body denervation improves autonomic and cardiac function and attenuates disordered breathing in congestive heart failure. J Physiol 592:391-408
Pellegrino, Peter R; Schiller, Alicia M; Zucker, Irving H (2014) Validation of pulse rate variability as a surrogate for heart rate variability in chronically instrumented rabbits. Am J Physiol Heart Circ Physiol 307:H97-109
Llewellyn, Tamra L; Sharma, Neeru M; Zheng, Hong et al. (2014) Effects of exercise training on SFO-mediated sympathoexcitation during chronic heart failure. Am J Physiol Heart Circ Physiol 306:H121-31
Sharma, Neeru M; Llewellyn, Tamra L; Zheng, Hong et al. (2013) Angiotensin II-mediated posttranslational modification of nNOS in the PVN of rats with CHF: role for PIN. Am J Physiol Heart Circ Physiol 305:H843-55
Zheng, Hong; Liu, Xuefei; Patel, Kaushik P (2013) Centrally mediated erectile dysfunction in rats with type 1 diabetes: role of angiotensin II and superoxide. J Sex Med 10:2165-76
Schiller, Alicia M; Haack, Karla K V; Pellegrino, Peter R et al. (2013) Unilateral renal denervation improves autonomic balance in conscious rabbits with chronic heart failure. Am J Physiol Regul Integr Comp Physiol 305:R886-92

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