Oxidant Stress in the Brain and Hypertension

Summary

Principal Investigator: Robin L Davisson
Abstract: DESCRIPTION (provided by applicant): Essential hypertension (HTN) is a major health problem, afflicting 30% of the population and predisposing to serious diseases affecting the brain, heart and kidneys. There is compelling evidence that essential HTN is characterized by neurohumoral dysfunction, and inappropriate angiotensin II (AngII) signaling in the central nervous system (CNS) is a primary culprit. The subfornical organ (SFO), a forebrain structure that lacks a blood-brain-barrier and is considered a key "gateway" to the CNS for circulating factors, is strongly implicated in AngII-dependent HTN. In previous cycles of this grant, we have shown that AngII (type 1 receptor, AT1R)- induced reactive oxygen species (ROS) signaling in the SFO mediates "slow-pressor" AngII HTN, a chronic mouse model that recapitulates key features of essential HTN. However, our understanding of how AngII- induced ROS formation in the SFO translates into powerful effects on neural pathways controlling blood pressure is still incomplete. Recently, endoplasmic reticulum (ER) stress has emerged as a major redox- associated mechanism in a number of cardiovascular and metabolic diseases;its role in HTN, however, is not known. AngII is now directly linked to ER stress in several cardiovascular cell types, and ER stress in the CNS leads to long-term changes in neural function through molecular mechanisms known to be involved in brain AngII-dependent HTN. During the past year, we have obtained exciting preliminary data showing links between AngII, ROS and ER stress in cultured neurons and in the SFO in vivo, along with evidence that chemical manipulation of ER stress in the CNS has significant effects on blood pressure. Based on these findings, we propose to test the overall hypothesis that ER stress in the SFO provides an important link between AngII, ROS and CNS alterations that lead to HTN in the AngII slow-pressor mouse model. Aim 1 will utilize molecular, immunocytochemical and ultrastructural analyses to test the hypothesis that AngII induces AT1R- dependent ER stress in the SFO in vivo. Aim 2 will test the hypothesis that the coupling of ER stress and oxidant stress is critical in slow-pressor AngII-mediated effects in the SFO. This will be accomplished through a combination of viral delivery of ROS scavengers, a genetic ER stress inhibitor and oxidative fluoroprobes for ROS measurements in the SFO in situ. Aim 3 will utilize SFO-targeted genetic manipulations of ER capacity combined with integrative cardiovascular physiology to test the hypothesis that ER stress in the SFO is a causal factor in slow-pressor AngII HTN and related neurohumoral sequelae. A notable strength of the project is the involvement of investigators with complementary expertise in central neural cardiovascular regulation and HTN (Davisson, Mark), ER stress biology (Kaufman, Qi), redox biology (Davisson, Kaufman) and neuroanatomy of CNS CV circuits (Pickel, Pierce). This project, which addresses a highly novel topic in HTN research, has the potential to fundamentally advance understanding of basic mechanisms linking the CNS with HTN, which could provide clues into novel treatments. The project also has the potential to forge new trails in HTN research.
Funding Period: 1999-12-01 - 2015-04-30
more information: NIH RePORT

Top Publications

  1. ncbi NADPH oxidases of the brain: distribution, regulation, and function
    David W Infanger
    Department of Anatomy and Cell Biology, Free Radical and Radiation Biology Program, The University of Iowa, Iowa City, 52245, USA
    Antioxid Redox Signal 8:1583-96. 2006
  2. pmc Inflaming hypothalamic neurons raises blood pressure
    Kamal Rahmouni
    Department of Internal Medicine, University of Iowa, Iowa City, IA, USA
    Cell Metab 14:3-4. 2011
  3. pmc Angiotensin II-dependent hypertension requires cyclooxygenase 1-derived prostaglandin E2 and EP1 receptor signaling in the subfornical organ of the brain
    Xian Cao
    Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY, USA
    Hypertension 59:869-76. 2012
  4. pmc Central cardiovascular circuits contribute to the neurovascular dysfunction in angiotensin II hypertension
    Carmen Capone
    Department of Neurology and Neuroscience, Division of Neurobiology, Weill Cornell Medical College, New York, New York 10021, USA
    J Neurosci 32:4878-86. 2012
  5. pmc Endothelin 1-dependent neurovascular dysfunction in chronic intermittent hypoxia
    Carmen Capone
    Division of Neurobiology, Department of Neurology and Neuroscience, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
    Hypertension 60:106-13. 2012
  6. pmc AAV-directed persistent expression of a gene encoding anti-nicotine antibody for smoking cessation
    Martin J Hicks
    Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA
    Sci Transl Med 4:140ra87. 2012
  7. pmc Distribution of angiotensin type 1a receptor-containing cells in the brains of bacterial artificial chromosome transgenic mice
    A D Gonzalez
    Division of Neurobiology, Department of Neurology and Neuroscience, Weill Cornell Medical College, 407 East 61st Street, New York, NY 10065, USA
    Neuroscience 226:489-509. 2012
  8. pmc ER stress in the brain subfornical organ mediates angiotensin-dependent hypertension
    Colin N Young
    Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853 6401, USA
    J Clin Invest 122:3960-4. 2012
  9. pmc Role of the NADPH oxidases in the subfornical organ in angiotensin II-induced hypertension
    Heinrich E Lob
    Department of Biomedical Sciences, Cornell University, Ithaca, NY, USA
    Hypertension 61:382-7. 2013
  10. pmc The brain subfornical organ mediates leptin-induced increases in renal sympathetic activity but not its metabolic effects
    Colin N Young
    Cornell University, Ithaca, NY 14853 6401, USA
    Hypertension 61:737-44. 2013

Research Grants

  1. Restoring Mycocardial Healing
    MARK ALAN SUSSMAN; Fiscal Year: 2013
  2. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
  3. Signaling Processes Underlying Cardiovascular Function
    Jeffrey Robbins; Fiscal Year: 2013
  4. Renin angiotensin system and connexin43
    Samuel C Dudley; Fiscal Year: 2013
  5. OXIDATIVE STRESS IN THE KIDNEY IN HYPERTENSION
    Christopher S Wilcox; Fiscal Year: 2013
  6. Interactions Between Inflammation, Oxidant Stress and Cardiovascular Disease
    David G Harrison; Fiscal Year: 2013
  7. Autonomic and Antihypertensive Actions of Neuronal CGRP/RAMP1 Receptors
    Mark W Chapleau; Fiscal Year: 2013
  8. Neutralizing Antibody &AAV FIX Gene Therapy
    Richard J Samulski; Fiscal Year: 2013

Detail Information

Publications28

  1. ncbi NADPH oxidases of the brain: distribution, regulation, and function
    David W Infanger
    Department of Anatomy and Cell Biology, Free Radical and Radiation Biology Program, The University of Iowa, Iowa City, 52245, USA
    Antioxid Redox Signal 8:1583-96. 2006
    ..In addition, perspectives for future research and novel therapeutic targets are offered...
  2. pmc Inflaming hypothalamic neurons raises blood pressure
    Kamal Rahmouni
    Department of Internal Medicine, University of Iowa, Iowa City, IA, USA
    Cell Metab 14:3-4. 2011
    ..A recent paper in Nature Medicine (Purkayastha et al., 2011) suggests that obesity and hypertension are caused by inflammation in distinct hypothalamic neuronal populations...
  3. pmc Angiotensin II-dependent hypertension requires cyclooxygenase 1-derived prostaglandin E2 and EP1 receptor signaling in the subfornical organ of the brain
    Xian Cao
    Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY, USA
    Hypertension 59:869-76. 2012
    ..Thus, COX 1-derived PGE(2) signaling through EP(1)R in the SFO is required for the ROS-mediated HTN induced by systemic infusion of Ang II and suggests that EP(1)R in the SFO may provide a novel target for antihypertensive therapy...
  4. pmc Central cardiovascular circuits contribute to the neurovascular dysfunction in angiotensin II hypertension
    Carmen Capone
    Department of Neurology and Neuroscience, Division of Neurobiology, Weill Cornell Medical College, New York, New York 10021, USA
    J Neurosci 32:4878-86. 2012
    ....
  5. pmc Endothelin 1-dependent neurovascular dysfunction in chronic intermittent hypoxia
    Carmen Capone
    Division of Neurobiology, Department of Neurology and Neuroscience, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
    Hypertension 60:106-13. 2012
    ..The ensuing cerebrovascular dysfunction may increase stroke risk in patients with sleep apnea by reducing cerebrovascular reserves and increasing the brain's susceptibility to cerebral ischemia...
  6. pmc AAV-directed persistent expression of a gene encoding anti-nicotine antibody for smoking cessation
    Martin J Hicks
    Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA
    Sci Transl Med 4:140ra87. 2012
    ..If this degree of efficacy translates to humans, AAVantiNic could be an effective preventative therapy for nicotine addiction...
  7. pmc Distribution of angiotensin type 1a receptor-containing cells in the brains of bacterial artificial chromosome transgenic mice
    A D Gonzalez
    Division of Neurobiology, Department of Neurology and Neuroscience, Weill Cornell Medical College, 407 East 61st Street, New York, NY 10065, USA
    Neuroscience 226:489-509. 2012
    ..These findings support the utility of Agtr1a BAC transgenic reporter mice for future studies understanding the role of AT(1)R-containing cells in brain function...
  8. pmc ER stress in the brain subfornical organ mediates angiotensin-dependent hypertension
    Colin N Young
    Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853 6401, USA
    J Clin Invest 122:3960-4. 2012
    ..To our knowledge, this is the first report that ER stress, notably brain ER stress, plays a key role in chronic HTN. Taken together, these findings may have broad implications for the pathophysiology of this disease...
  9. pmc Role of the NADPH oxidases in the subfornical organ in angiotensin II-induced hypertension
    Heinrich E Lob
    Department of Biomedical Sciences, Cornell University, Ithaca, NY, USA
    Hypertension 61:382-7. 2013
    ....
  10. pmc The brain subfornical organ mediates leptin-induced increases in renal sympathetic activity but not its metabolic effects
    Colin N Young
    Cornell University, Ithaca, NY 14853 6401, USA
    Hypertension 61:737-44. 2013
    ..These findings highlight the concept of a distributed brain network of leptin action and illustrate that brain regions, including the SFO, can mediate distinct cardiovascular and metabolic responses to leptin...
  11. pmc Nox2 and Nox4 influence neonatal c-kit(+) cardiac precursor cell status and differentiation
    Alyson S Nadworny
    Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, New York and
    Am J Physiol Heart Circ Physiol 305:H829-42. 2013
    ..We speculate that ROS generators Nox2 and Nox4, along with the antioxidant genes identified by PCR Arrays, may be novel targets in CPCs that could prove useful in cell-based therapy of the heart...
  12. pmc Selective leptin resistance revisited
    Allyn L Mark
    Department of Internal Medicine and the Obesity Research and Education Initiative, University of Iowa Carver College of Medicine, Iowa City, Iowa
    Am J Physiol Regul Integr Comp Physiol 305:R566-81. 2013
    ..Finally, I review perplexing data on the effects of leptin on sympathetic activity and BP in humans and its role in human obesity-induced hypertension. ..
  13. pmc COX-1-derived PGE2 and PGE2 type 1 receptors are vital for angiotensin II-induced formation of reactive oxygen species and Ca(2+) influx in the subfornical organ
    Gang Wang
    The Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York
    Am J Physiol Heart Circ Physiol 305:H1451-61. 2013
    ..Our findings provide the first evidence of a spatial and functional framework that underlies ANG-II signaling in the SFO and reveal novel targets for antihypertensive therapies...
  14. pmc In vivo assessment of neurocardiovascular regulation in the mouse: principles, progress, and prospects
    Colin N Young
    Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853 6401, USA
    Am J Physiol Heart Circ Physiol 301:H654-62. 2011
    ..The advantages and limitations of each methodology are highlighted to allow for a critical evaluation by the reader when considering these approaches...
  15. pmc In vivo bioluminescence imaging reveals redox-regulated activator protein-1 activation in paraventricular nucleus of mice with renovascular hypertension
    Melissa A Burmeister
    Biomedical Sciences, College of Veterinary Medicine, Weill Cornell Medical College, Cornell University, Ithaca, NY 14853 6401, USA
    Hypertension 57:289-97. 2011
    ..These results implicate oxidant signaling and AP-1 transcriptional activity in the PVN as key mediators in the pathogenesis of renovascular hypertension...
  16. ncbi Genetic ablation of angiotensinogen in the subfornical organ of the brain prevents the central angiotensinergic pressor response
    Puspha Sinnayah
    Department of Anatomy and Cell Biology, Roy J and Lucille A Carver College of Medicine, The University of Iowa, Iowa City, USA
    Circ Res 99:1125-31. 2006
    ....
  17. pmc Local production of angiotensin II in the subfornical organ causes elevated drinking
    Koji Sakai
    Department of Internal Medicine, Department of Anatomy and Cell Biology, and Center on Functional Genomics of Hypertension, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA
    J Clin Invest 117:1088-95. 2007
    ..These data provide strong genetic evidence implicating de novo synthesis of Ang II in the SFO as an integral player in fluid homeostasis...
  18. ncbi Central overexpression of angiotensin AT(1A) receptors prevents dopamine D(2) receptor regulation of alcohol consumption in mice
    Rosanna Moore
    Howard Florey Institute, University of Melbourne, Parkville, Vic, Australia
    Alcohol Clin Exp Res 31:1128-37. 2007
    ..While angiotensin receptors are found on the soma and terminals of dopaminergic neurons, controversy surrounds the potential role of angiotensin in alcohol consumption...
  19. ncbi Longitudinal noninvasive monitoring of transcription factor activation in cardiovascular regulatory nuclei using bioluminescence imaging
    Jeffrey R Peterson
    Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853 6401, USA
    Physiol Genomics 33:292-9. 2008
    ..These results demonstrate that BLI, in combination with virally mediated gene transfer, is a powerful method for longitudinal monitoring and quantification of TF activity in targeted CNS nuclei in vivo...
  20. pmc Hypertension and cerebrovascular dysfunction
    Costantino Iadecola
    Division of Neurobiology, Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, NY 10021, USA
    Cell Metab 7:476-84. 2008
    ..This review focuses on the mechanisms by which hypertension disrupts cerebral blood vessels, highlighting recent advances and outstanding issues...
  21. pmc Cardiovascular responses to peripheral chemoreflex activation and comparison of different methods to evaluate baroreflex gain in conscious mice using telemetry
    Valdir A Braga
    Dept of Biomedical Sciences, College of Veterinary Medicine, Weill Cornell Medical College, T9 014 Veterinary Research Tower, Cornell Univ, Ithaca, NY 14853 6401, USA
    Am J Physiol Regul Integr Comp Physiol 295:R1168-74. 2008
    ..However, for absolute determination of baroreflex function, analysis of spontaneous baroreflex activity should be complemented by the classical pharmacological method...
  22. pmc Enhanced water and salt intake in transgenic mice with brain-restricted overexpression of angiotensin (AT1) receptors
    Eric Lazartigues
    Department of Anatomy and Cell Biology, The University of Iowa, Iowa City, Iowa, USA
    Am J Physiol Regul Integr Comp Physiol 295:R1539-45. 2008
    ..This model provides a new tool for studying the mechanisms of brain AT(1A)-dependent water and salt consumption...
  23. pmc Scavenging superoxide selectively in mouse forebrain is associated with improved cardiac function and survival following myocardial infarction
    Timothy E Lindley
    Department of Anatomy, The University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, Iowa, USA
    Am J Physiol Regul Integr Comp Physiol 296:R1-8. 2009
    ..This suggests that oxidative stress in the SFO plays a critical role in the deterioration of cardiac function following MI and underscores the promise of CNS-targeted antioxidant therapy for the treatment of MI-induced HF...
  24. pmc Genetic silencing of Nox2 and Nox4 reveals differential roles of these NADPH oxidase homologues in the vasopressor and dipsogenic effects of brain angiotensin II
    Jeffrey R Peterson
    Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY, USA
    Hypertension 54:1106-14. 2009
    ....
  25. pmc Silencing nox4 in the paraventricular nucleus improves myocardial infarction-induced cardiac dysfunction by attenuating sympathoexcitation and periinfarct apoptosis
    David W Infanger
    Professor of Molecular Physiology, Biomedical Sciences and Cell and Developmental Biology, Cornell University, T9 014 Veterinary Research Tower, Ithaca, NY 14853 6401, USA
    Circ Res 106:1763-74. 2010
    ....
  26. pmc The cerebrovascular dysfunction induced by slow pressor doses of angiotensin II precedes the development of hypertension
    Carmen Capone
    Division of Neurobiology, Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, New York, USA
    Am J Physiol Heart Circ Physiol 300:H397-407. 2011
    ....
  27. pmc Emerging concepts in hypertension
    Joseph Francis
    1 Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana
    Antioxid Redox Signal 20:69-73. 2014
    ..Finally, we explore the clinical relevance of increased ROS in the setting of human hypertension...

Research Grants30

  1. Restoring Mycocardial Healing
    MARK ALAN SUSSMAN; Fiscal Year: 2013
    ..The goal of this program will be to delineate these deleterious signaling mechanisms and determine how they can be overcome to restore endogenous cellular repair processes that heal the damaged heart. ..
  2. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  3. Signaling Processes Underlying Cardiovascular Function
    Jeffrey Robbins; Fiscal Year: 2013
    ..These projects are supported by 3 Cores: Core A: The Administrative Core;Core B: The Physiology Core and Core C: The Imaging-Cell Culture Core. (End of Abstract) ..
  4. Renin angiotensin system and connexin43
    Samuel C Dudley; Fiscal Year: 2013
    ..Specifically, this application will give a more complete picture of the pro-arrhythmic effects of AngII on heart, which could lead to new diagnostic and therapeutic interventions. ..
  5. OXIDATIVE STRESS IN THE KIDNEY IN HYPERTENSION
    Christopher S Wilcox; Fiscal Year: 2013
    ..These are supported by the Administrative, Animal and Bioanalytical Cores. ..
  6. Interactions Between Inflammation, Oxidant Stress and Cardiovascular Disease
    David G Harrison; Fiscal Year: 2013
    ..Overall, these studies will promote our understanding of the interplay between inflammation, oxidant stress and cardiovascular disease. ..
  7. Autonomic and Antihypertensive Actions of Neuronal CGRP/RAMP1 Receptors
    Mark W Chapleau; Fiscal Year: 2013
    ..Inhibition of Ang II-mediated effects by activation of CGRP/RAMP1 receptors has widespread implications in hypertension and heart failure. ..
  8. Neutralizing Antibody &AAV FIX Gene Therapy
    Richard J Samulski; Fiscal Year: 2013
    ..The long-term objective of this PPG is to advance basic understanding of vector-cell-animal model interactions for safe gene delivery. ..