The carotid body (CB) chemoreflex is enhanced in chronic heart failure (CHF) and contributes to the chronic elevation in sympathetic nerve activity (SNA). This enhanced functionality is driven by an increased activity from CB chemoafferents, resulting from alterations in redox signaling within the CB from enhanced angiotensin II (Ang II) -NADPH oxidase - super oxide anion (O2*"), and attenuated neural and endothelial nitric oxide synthase (nNOSI/eNOS) - nitric oxide (NO) that synergistically inhibit Kv* channel currents in CB glomus cells and increase excitability. Recent evidence suggests Ang 1-7 derived from ACE2, inhibits CB chemoafferent activity and is down regulated by CHF. Exercise training (ExT) reverses these alterations in CB function in CHF. The stimuli for these altered signaling pathways in the CB in CHF and their reversal with ExT is unknown. We propose in Aim 1 that Ang 1-7 produced in the CB normally acts via the Mas receptor to activate nNOS - NO production in glomus cells to restrain excitability, via activation of Kv* currents and inhibition of high voltage activated Ca** currents. We propose that CHF downregulates ACE2 while up regulating ACE to shift Ang metabolism away from Ang 1-7/NO toward Ang 11/ O2" signaling at glomus cells to promote enhanced afferent function. The relative contributions of ACE and ACE2 to CB function in CHF will be tested.
In Aim 2. we propose the fundamental hypothesis that a chronic decrease in CB blood flow (CBF) due to cardiac failure and CB vasoconstriction alters endothelial ACE, ACE2 and NOS function in the CB to effect the altered Ang/NO signaling at glomus cells discussed above. We propose that upregulation of ACE, and downregulation of ACE2 / eNOS expression in the CB in CHF is caused by a decreased transcriptional activity of the kruppel like factor 2 (KLF2) triggered by a reduction in shear stress on CB endothelial cells. Lastly, we hypothesize in Aim 3 that the normalizing effect of ExT on CB function in CHF is brought about by regular periodic increases in CBF during exercise to improve endothelial KLF2, ACE, ACE2 and eNOS, expression, and thus, restore normal Ang/NO balance and control of K*/Ca** channels in glomus cells, effecting CB function. These hypotheses will be tested at four levels: integrative (CB chemoreflex changes in SNA and ventilation);tissue (CB chemoafferent discharge);cellular (ion channel currents in CB glomus cells);and molecular (mRNA/protein expression in the CB, immunohistochemistry for localization), using genomic (overexpression of mediators via viral vectors localized to the CB) and pharmacological approaches in models of pacing-induced CHF and of chronic reduced CBF in rabbits.

Public Health Relevance

This proposal addresses the molecular pathway for altered CB function in CHF via the angiotensin and nitric oxide systems. We propose these changes result from reduced blood flow to the CB in CHF to alter endothelial expression of ACE, ACE2 and NOS via the KLF2 transcription factor. Furthermore, the beneficial effect of ExT on CB function in CHF may result from improved blood flow to the CB. Outcomes may impact clinical management of CHF through more targeted pharmacological/genomic approaches and a better understanding of the actions of exercise as a therapeutic modality. 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)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Nebraska Medical Center
United States
Zip Code
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

Showing the most recent 10 out of 110 publications