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 #
5P01HL062222-15
Application #
8509760
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
2013-09-01
Budget End
2014-08-31
Support Year
15
Fiscal Year
2013
Total Cost
$1,743,500
Indirect Cost
$569,426
Name
University of Nebraska Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Tian, Changhai; Gao, Lie; Zimmerman, Matthew C et al. (2018) Myocardial infarction-induced microRNA-enriched exosomes contribute to cardiac Nrf2 dysregulation in chronic heart failure. Am J Physiol Heart Circ Physiol 314:H928-H939
Marcus, Noah J; Del Rio, Rodrigo; Ding, Yanfeng et al. (2018) KLF2 mediates enhanced chemoreflex sensitivity, disordered breathing and autonomic dysregulation in heart failure. J Physiol 596:3171-3185
Fontes, Marco Antônio Peliky; Vaz, Gisele Cristiane; Cardoso, Thais Zielke Dias et al. (2018) GABA-containing liposomes: neuroscience applications and translational perspectives for targeting neurological diseases. Nanomedicine 14:781-788
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Zheng, Hong; Katsurada, Kenichi; Liu, Xuefei et al. (2018) Specific Afferent Renal Denervation Prevents Reduction in Neuronal Nitric Oxide Synthase Within the Paraventricular Nucleus in Rats With Chronic Heart Failure. Hypertension 72:667-675
Lewis, Robert; Hackfort, Bryan T; Schultz, Harold D (2018) Chronic Heart Failure Abolishes Circadian Rhythms in Resting and Chemoreflex Breathing. Adv Exp Med Biol 1071:129-136
Mishra, Paras K; Ying, Wei; Nandi, Shyam Sundar et al. (2017) Diabetic Cardiomyopathy: An Immunometabolic Perspective. Front Endocrinol (Lausanne) 8:72
Sharma, Neeru M; Patel, Kaushik P (2017) Post-translational regulation of neuronal nitric oxide synthase: implications for sympathoexcitatory states. Expert Opin Ther Targets 21:11-22
Schultz, Harold D (2017) Epigenetic influences on carotid body function: a new snag in the road to treating sleep apnoea. J Physiol 595:629-630
Gao, Lie; Zimmerman, Matthew C; Biswal, Shyam et al. (2017) Selective Nrf2 Gene Deletion in the Rostral Ventrolateral Medulla Evokes Hypertension and Sympathoexcitation in Mice. Hypertension 69:1198-1206

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