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Principal Investigator: Eric D Lazartigues
Organization: SOUTHEAST LOUISIANA VETERANS HEALTH CARE
Fiscal Year: 2021
Funding agency: Veterans Affairs
With prevalence higher than 33% in United States, hypertension is a major risk factor contributing
to cardiovascular diseases (CVD) and global mortality, hence remaining an increasingly important
medical and public health issue. According to the Veterans’ Affairs (VA) Office of Research &
Development, CVD, including hypertension, are the number-one killer in the USA, the leading
cause of hospitalization in the VA health care system and a major cause of disability. Recent
studies have documented that hypertension occurs at a younger age than it used to, now affecting
individuals of deployment age and future veterans. Hypertension is also important to Veterans
because it affects 60 percent of people over age 65 and it is associated with a number of diseases,
like diabetes, and lifestyle habits, like smoking, that contribute to its development. The role of the
brain renin-angiotensin system (RAS) in the maintenance of normal blood pressure (BP) and in
the neuro-cardiovascular dysregulation leading to hypertension has been firmly established.
Angiotensin (Ang)-II, by means of its type 1 receptor (AT1R), promotes increased sympathetic
activity, salt and water reabsorption, vasoconstriction, aldosterone and vasopressin release and
inflammation, all contributing to hypertension. Angiotensin Converting Enzyme type 2 (ACE2),
one of the latest identified members of this system plays a compensatory role to the activation of
the RAS. Numerous studies have shown that ACE2 overexpression prevents experimental
hypertension. However, our laboratory reported that Ang-II mediates ACE2 internalization and
degradation via AT1R activation, effects that were prevented by pretreatment with leupeptin, a
lysosomal inhibitor. The detailed mechanism leading to the loss of ACE2 compensatory activity
has not been investigated. This proposal aims at targeting this new mechanism responsible for
ACE2 down-regulation, originally described by our group, to design innovative strategies for the
treatment of hypertension. The efficacy of these strategies will be evaluated by their ability to
prevent ACE2 internalization and preserve ACE2 compensatory in the context of neurogenic
hypertension. Our preliminary data, show that ubiquitination of the C-terminus of ACE2 is a major
mechanism leading to ACE2 degradation. In addition, stimulation of the β-arrestin pathway with
an AT1R-biased agonist increased ACE2 activity in neurons. Finally, ACE2 internalization may
involve other members of the G-protein coupled receptor family (GPCR), like bradykinin B1
receptors (B1R) interacting with the RAS. Thus, the hypothesis of this work is that AT1R and B1R
blunts ACE2 compensatory activity through multiple binding partners affecting its expression
levels, subcellular localization and enzymatic activity. Pharmacological and genetic targeting of
these binding partners may constitute a novel approach to maintain ACE2 compensatory activity
and reduce hypertension. To test this hypothesis, we will use state-of-the-art in vitro and in vivo,
molecular, cellular and pharmacological tools combined with unique transgenic and knockout
models of hypertension. The results of the present investigation will provide new therapeutic
approaches for the treatment of hypertension and a new set of tools for the VA health care system.
Terms: <65+ years old><ACE2><APLN><APLN gene><Address><Affect><Age><Aged 65 and Over><Agonist><Aldosterone><Ang I (1-7)><AngII><Angiotensin Converting Enzyme><Angiotensin I-Converting Enzyme><Angiotensin II><Antidiuretic Hormone><Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg><Attenuated><Avandia><Binding><Blood Pressure><Bradykinin><Brain><Brain Nervous System><CD143 Antigens><Carboxycathepsin><Cardiovascular><Cardiovascular Body System><Cardiovascular Diseases><Cardiovascular Organ System><Cardiovascular system><Cleaved cell><Data><Development><Development and Research><Diabetes Mellitus><Dipeptidyl Peptidase A><Disease><Disorder><Down-Regulation><Downregulation><Encephalon><Enzyme Gene><Enzymes><Experimental Models><Family><Future><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G-Protein-Coupled Receptors><GEM model><GPCR><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genetically Engineered Mouse><Habits><Health Care Systems><Healthcare Systems><Heart Vascular><High Prevalence><Hospital Admission><Hospitalization><Hydrogen Oxide><Hypertension><Hypothalamic structure><Hypothalamus><Impairment><In Vitro><Individual><Inflammation><Inflammatory><Investigation><Kininase A><Kininase II><Knock-out><Knockout><L-Lysine><Laboratories><Leupeptins><Life Style><Lifestyle><Losartan><Lysine><Lysosomes><Maintenance><Mediating><Medical><Modeling><Molecular><Molecular Interaction><Mutation><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Opiate Peptides><Opioid Peptide><PPAR><PPAR gamma><PPAR-γ><PPARgamma><PPARγ><Pathway interactions><Peptides><Peptidyl-Dipeptidase A><Peroxisome Proliferative Activated Receptor Gamma><Peroxisome Proliferator-Activated Receptor gamma><Peroxisome Proliferator-Activated Receptor γ><Peroxisome Proliferator-Activated Receptors><Pharmacology><Play><Public Health><R & D><R&D><Receptor Protein><Renin-Angiotensin System><Reporting><Risk Factors><Role><Site><Smoking><Sodium Chloride><System><Telemetries><Telemetry><Testing><Therapeutic><Thiazolidinedione Receptor><Time><Transgenic Organisms><Ubiquitilation><Ubiquitination><Ubiquitinoylation><United States><United States Department of Veterans Affairs><United States Veterans Administration><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Vasodilating Agent><Vasodilator Agents><Vasodilator Drugs><Vasodilators><Vasopressins><Veterans><Veterans Administration><Veterans Affairs><Veterans Health Administration><Veterans Health Affairs><Water><Work><age 65 and greater><age 65 and older><aged 65 and greater><aged ≥65><ages><angiotensin I (1-7)><angiotensin converting enzyme 2><angiotensin converting enzyme II><angiotensin-(1-7)><apelin><arrestin B><base><beta-Hypophamine><beta-arrestin><cardiovascular disorder><circulatory system><cleaved><conditional knock-out><conditional knockout><design><designing><developmental><diabetes><disability><genetically engineered mouse model><genetically engineered murine model><genome mutation><high blood pressure><human old age (65+)><hyperpiesia><hyperpiesis><hypertension treatment><hypertensive disease><hypothalamic><improved><in vivo><inhibitor><inhibitor/antagonist><innovate><innovation><innovative><kallidin 9><kallidin I><lozartan><member><mortality><mouse model><murine model><neurogenic hypertension><neuronal><new approaches><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><novel><novel approaches><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><old age><optogenetics><overexpress><overexpression><pathway><preservation><prevent><preventing><receptor><research and development><response><rosiglitazone><salt><social role><tool><transgenic><treatment strategy><ubiquination><ubiquitin conjugation><vascular constriction><vasoconstriction><β-arrestin>