This Program Project Grant (PPG) renewal describes a series of experiments designed to answer highly relevant questions concerning the mechanisms for sympatho-excitation in chronic heart failure (CHF). There has been a long history of interaction among the Pi's in this PPG. We have contributed substantially to the literature in this area and are now proposing new studies that probe deeper into the origins of sympathetic regulation in CHF. Overall, we believe that sympathetic activation is mediated by a combination of increased sympatho-excitatory reflexes, blunted sympatho-inhibitory reflexes and changes in signaling molecules in the central nervous system and in the periphery. Four projects are proposed. In Project I the focus will be on the mechanism by which the ATiR is upregulated in the RVLM of animals with heart failure. This unique property of a GPCR to be upregulated in the face of increased agonist (Ang II) suggests a pivotal role for this receptor in the pathogenesis of sympatho-excitation in CHF. We will determine alterations in transcriptional regulation of the ATiR and the roles of ACE, ACE2, ROS and exercise training. Project II will focus on the role of the PVN in sympathetic regulation. Building on studies showing abnormalities in the GABA-glutamate systems in the PVN, this project now proposes that an ascending noradrenergic pathway modulated, in part, by aldosterone plays an important role in sympatho-excitation in CHF. The interactions between aldosterone and nNOS will be examined in this project. Finally, the role of exercise training on nNOS and aldosterone in CHF will be investigated. Project III concentrates on the sensitized carotid chemoreflex in CHF. This project has clearly shown chemoreceptor and chemoreflex sensitization in CHF and an important role for K* channel modulation in glomus cells by Ang II and NO in response to hypoxia. This project now focuses on the role of altered carotid body blood flow as a mediator of chemoreflex sensitivity. These studies will investigate the role of a novel transcription factor, KLF2, in mediating transduction between endothelial shear stress and mediators of K* channel function. The role of Ang (1-7) will also be investigated in this project. Project IV will investigate the role of skeletal muscle reflexes on sympatho-excitation in CHF. Specifically, this project will determine if ROS play an important role in altering the sensitivity of both chemically sensitive group III afferents and mechanically sensitive group IV afferents. The role of exercise training in modulating ROS generation and antioxidant enzymes in animals with CHF will also be investigated in this project.

Public Health Relevance

Chronic heart failure is a growing concern as the aging population of the United States increases. New Strategies in the treatment of heart failure must be developed. This PPG is important and highly relevant to the heart failure epidemic in that it addresses a relatively neglected area of patho-physiology, namely sympathetic nerve, activation. These studies will uncover new mechanisms and new potential targets for therapy in the heart failure state.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL062222-14
Application #
8287500
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Lathrop, David A
Project Start
1999-07-05
Project End
2014-08-31
Budget Start
2012-07-01
Budget End
2013-08-31
Support Year
14
Fiscal Year
2012
Total Cost
$1,831,407
Indirect Cost
$598,136
Name
University of Nebraska Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
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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