Chronic heart failure (CHF) is one of the leading causes of death in the U.S. A primary characteristic of this disease is elevated sympatho-excitation and exercise intolerance during physical activity. During exercise in heart failure patients, extreme activation of the sympathetic nervous system is often seen and evokes an exaggerated pressor response accompanied by hyperventilation. These abnormalities potentially increase cardiovascular risk during physical activity in these patients. Experimental evidence suggests that 1) the exaggerated sympatho-excitation during exercise is directly related to an increased sensitivity of the exercise pressor reflex (EPR); and 2) the enhanced mechanically sensitive afferent component of this reflex (i.e. mechanoreflex) primarily contributes to the exaggerated EPR in CHF. The molecular and cellular mechanisms underlying the selective sensitization of the mechano-sensitive afferent limb in CHF has not fully understood. Here, we propose to test a novel hypothesis that neurotrophins (especially brain-derived neurotrophic factor, BDNF) in muscle afferent neurons play a critical role in the sensitization of the mechanical afferent limb of the EPR in CHF. We believe that this pathway operates by a mitogen-activated protein kinase (MAPK)-K+ channel mechanism. Due to underperfusion of skeletal muscle in CHF there is release of reactive oxygen species and inflammation. These stress in afferent terminal endings may stimulate muscle afferent neurons in lumbar dorsal root ganglia (DRGs) to generate neurotrophins for survival. However, effects of BDNF separate from its neurotrophic properties may also increase neuronal excitability and terminal sensitivity by activating MAPK pathways and modulating the electrical properties of voltage-gated ion channels such as K+ channels. We will use highly integrative techniques including molecular (real-time PCR, western blot, immunofluorescence and viral transfection), cellular (patch clamp) and whole animal experiments (measuring EPR function, single afferent recording) to test the BDNF hypothesis in this project. We believe that this proposed research will address important functional and mechanistic issues that directly relate to the quality of lif in patients with CHF. These data will uncover new targets for therapy in this patient population.

Public Health Relevance

A hallmark feature of chronic heart failure (CHF) is decreased exercise tolerance and elevated sympathetic nerve activity at rest and during acute exercise, which limits the exercise capacity of these patients and contributes to the deterioration in cardiovascular function. The primary goal of the proposed research is to explore the contribution of Brain Derived Neurotropic Factor (BDNF) in mediating the exaggerated exercise pressor reflex (EPR) as well as the mechanical afferent sensitization of the EPR in CHF. These data will be important in developing therapies for reducing cardiovascular dysfunction in CHF.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL121012-01A1
Application #
9104984
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Schwartz, Lisa
Project Start
2016-04-06
Project End
2020-03-31
Budget Start
2016-04-06
Budget End
2017-03-31
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Nebraska Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Shanks, Julia; Xia, Zhiqiu; Lisco, Steven J et al. (2018) Sympatho-excitatory response to pulmonary chemosensitive spinal afferent activation in anesthetized, vagotomized rats. Physiol Rep 6:e13742
Wang, Han-Jun (2017) Mineralocorticoids: the secret of muscle reflex dysfunction in hypertension? Am J Physiol Heart Circ Physiol 313:H931-H933
Wang, Hanjun; Case, Adam J; Wang, Wei-Zhong et al. (2016) Redox Signaling and Neural Control of Cardiovascular Function. Oxid Med Cell Longev 2016:7086018
Becker, Bryan K; Tian, Changhai; Zucker, Irving H et al. (2016) Influence of brain-derived neurotrophic factor-tyrosine receptor kinase B signalling in the nucleus tractus solitarius on baroreflex sensitivity in rats with chronic heart failure. J Physiol 594:5711-25