title: Brain-selective overexpression of human Angiotensin-converting enzyme type 2 attenuates neurogenic hypertension.
abstract: BACKGROUND
  Angiotensin converting enzyme type 2 (ACE2) is a new member of the brain renin-angiotensin system, that might be activated by an overactive renin-angiotensin system.
  
  
  OBJECTIVE
  To clarify the role of central ACE2 using a new transgenic mouse model with human (h)ACE2 under the control of a synapsin promoter, allowing neuron-targeted expression in the central nervous system.
  
  
  RESULTS
  Syn-hACE2 (SA) transgenic mice exhibit high hACE2 protein expression and activity throughout the brain. Baseline hemodynamic parameters (telemetry), autonomic function, and spontaneous baroreflex sensitivity (SBRS) were not significantly different between SA mice and nontransgenic littermates. Brain-targeted ACE2 overexpression attenuated the development of neurogenic hypertension (Ang II infusion: 600 ng/kg per minute for 14 days) and the associated reduction of both SBRS and parasympathetic tone. This prevention of hypertension by ACE2 overexpression was reversed by blockade of the Ang-(1-7) receptor (d-Ala7-Ang-[1-7]; 600 ng/kg per minute). Brain angiotensin II type 2 (AT(2))/AT(1) and Mas/AT(1) receptor ratios were significantly increased in SA mice. They remained higher following Ang II infusion but were dramatically reduced after Ang-(1-7) receptor blockade. ACE2 overexpression resulted in increased NOS and NO levels in the brain, and prevented the Ang II-mediated decrease in NOS expression in regions modulating blood pressure regulation.
  
  
  CONCLUSIONS
  ACE2 overexpression attenuates the development of neurogenic hypertension partially by preventing the decrease in both SBRS and parasympathetic tone. These protective effects might be mediated by enhanced NO release in the brain resulting from Mas and AT(2) receptor upregulation. Taken together, our data highlight the compensatory role of central ACE2 and its potential benefits as a therapeutic target for neurogenic hypertension.
authors.affiliation: Louisiana State University Health Sciences Center, School of Medicine, Department of Pharmacology and Experimental Therapeutics, 1901 Perdido St, New Orleans, LA 70112, USA.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Feng
authors.forename: Huijing
authors.initials: H
authors.lastname: Xia
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Cai
authors.forename: Carmen M
authors.initials: CM
authors.lastname: Halabi
authors.forename: Lenice K
authors.initials: LK
authors.lastname: Becker
authors.forename: Robson A S
authors.initials: RA
authors.lastname: Santos
authors.forename: Robert C
authors.initials: RC
authors.lastname: Speth
authors.forename: Curt D
authors.initials: CD
authors.lastname: Sigmund
authors.forename: Eric
authors.initials: E
authors.lastname: Lazartigues
mesh_terms: D000804:Angiotensin II / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D017704:Baroreflex / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D001921:Brain / Q000201:enzymology / Q000378:metabolism*; D001933:Brain Stem / Q000201:enzymology / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D006973:Hypertension / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D010275:Parasympathetic Nervous System / Q000502:physiology; D010446:Peptide Fragments / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000235:genetics* / Q000378:metabolism; D011945:Receptors, Angiotensin / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D010446:Peptide Fragments; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2