Nrf2: Neuronal Oxidative Stress and SNA in Heart Failure

NIH Pandemic-Era Grants

Pandemic Era Grants

2019

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Principal Investigator: Irving H Zucker
Organization: UNIVERSITY OF NEBRASKA MEDICAL CENTER
Fiscal Year: 2019
Award: $437,136
Funding agency: National Heart Lung and Blood Institute

PROJECT SUMMARY/ABSTRACT
Chronic heart failure (CHF) affects a growing number of Americans. This disease is one of the leading causes
of death and disability in the developed world. In order to develop new therapies for this disorder a
comprehensive understanding of the pathogenesis and mechanisms behind CHF is critically important.
Activation of the sympathetic nervous system is almost pathognomonic of CHF. Over the past 16 years we
have investigated the central origins of sympatho-excitation in CHF. We have focused on the brain renin-
Angiotensin II system with specific emphasis on the Angiotensin Type 1 receptor (AT1R) and its role in the
generation of oxidative stress. We have shown that the transcriptional regulation of AT1R expression is
mediated by NFkB in addition to several other downstream transcription factors in tissue extracted from the
rostral ventrolateral medulla (RVLM). In the current project we focus on a new and potentially important
mechanism in the generation of neuronal oxidative stress in the CHF state. We propose that the transcription
factor Nrf2 is decreased in RVLM tissue from CHF animals. Importantly, we propose that the decrease in Nrf2
and its effects on antioxidant enzyme transcription is mediated, in part, by competition with NFkB for binding to
the CREB binding protein (CBP) in the nucleus. We also propose that influences external to the cell such as
exercise training and the balance between ACE and ACE2 may be important modulators of Nrf2 and oxidative
stress in CHF. We will use rat and mouse CHF models. Novel transgenic mouse models will be used to
address four specific aims. Specific Aim 1 will determine the role of Nrf2 in the regulation of oxidative stress in
the RVLM and its impact on sympatho-excitation in CHF. We hypothesize that a decrease in Nrf2 in the RVLM
contributes to increased oxidative stress and sympathetic nerve activity of animals with CHF. Specific Aim 2
will determine the relationships between Nrf2 and NFkB on the regulation of oxidative stress and AT1R
expression in the RVLM of animals with CHF. We hypothesize that increased binding to CBP by NFkB in the
RVLM of animals with CHF will result in an upregulation of AT1R and increased oxidative stress and
contributes to sympatho-excitation. In addition, we hypothesize that upregulation of Nrf2 will displace NFkB
from CBP thus contributing to a decrease in AT1R and an upregulation of antioxidant enzymes. Specific Aim
3 will demonstrate that ExT decreases oxidative stress, AT1R expression, sympathetic nerve activity and
RVLM discharge by a Nrf2-dependent mechanism in CHF. We hypothesize that ExT reduces Nrf2
ubiquitination and reduces the NFkB arm of this pathway. Specific Aim 4 will determine if ACE2 reduces
oxidative stress in the RVLM by activation of Nrf2. In addition, we will show that overexpression and
knockdown of ACE2 in novel mouse models alters the effects of ExT on Nrf expression and activity. These
studies will be thematically interactive with Projects 1and 3.

Terms: <Active Oxygen><Address><Affect><Age-Years><American><AngII><Angiotensin AT1 Receptor><Angiotensin Converting Enzyme><Angiotensin I-Converting Enzyme><Angiotensin II><Angiotensin II Type 1 Receptor><Angiotensin-Forming Enzyme><Angiotensinogenase><Animals><Area><Basal Transcription Factor><Basal transcription factor genes><Binding><Body Tissues><Brain><Brain Nervous System><CBP gene><CBP protein><CD143 Antigens><CREB-binding protein><CREBBP><CREBBP gene><Carboxycathepsin><Cardiac><Cardiac Failure Congestive><Cardiovascular Diseases><Cause of Death><Cell Body><Cell Communication and Signaling><Cell Nucleus><Cell Signaling><Cells><Common Rat Strains><Congestive Heart Failure><Data><Devices><Diagnosis><Dipeptidyl Peptidase A><Disease><Disorder><Down-Regulation><Downregulation><Dysfunction><Encephalon><Epidemic><Equilibrium><Erythroid><Event><Feedback><Functional disorder><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Generations><Genetic><Genetic Technics><Genetic Techniques><Genetic Transcription><Heart Decompensation><Heart failure><Hospital Admission><Hospitalization><Human><Impairment><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Kininase A><Kininase II><Link><LoxP-flanked allele><Mediating><Mediator><Mediator of Activation><Mediator of activation protein><Methods><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Interaction><Murine><Mus><Nerve><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Nuclear><Nucleus><Operative Procedures><Operative Surgical Procedures><Organ><Oxidation-Reduction><Oxidative Regulation><Oxidative Stress><Oxygen Radicals><Pathogenesis><Pathway interactions><Patient Admission><Peptidyl-Dipeptidase A><Peripheral><Pharmacology><Phase><Physiologic><Physiological><Physiopathology><Play><Pro-Oxidants><Process><RNA Expression><Rat><Rats Mammals><Rattus><Reactive Oxygen Species><Receptor, Angiotensin, Type 1><Redox><Regulation><Renin><Role><Signal Transduction><Signal Transduction Systems><Signaling><Surgical><Surgical Interventions><Surgical Procedure><Sympathetic Nervous System><System><Tissue Extracts><Tissues><Transcription><Transcription Factor Proto-Oncogene><Transcription Regulation><Transcription factor genes><Transcriptional Control><Transcriptional Regulation><Transgenic Mice><Ubiquitilation><Ubiquitination><Ubiquitinoylation><United States><Up-Regulation><Upregulation><Work><aged population><aging population><anti-oxidant enzyme><antioxidant enzyme><arm><balance><balance function><biological signal transduction><cardiac failure><cardiovascular disorder><chronic heart failure><disability><exercise training><experiment><experimental research><experimental study><floxed><floxed allele><interventional strategy><knock-down><knockdown><mortality><mouse model><murine model><neglect><neuronal><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel therapeutics><novel therapy><overexpress><overexpression><oxidation reduction reaction><pathophysiology><pathway><population aging><receptor expression><receptor upregulation><response><social role><surgery><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><transcription factor><ubiquination><ubiquitin conjugation>