title: Brain angiotensin-converting enzyme type 2 shedding contributes to the development of neurogenic hypertension.
abstract: BACKGROUND
  Overactivity of the brain renin-angiotensin system is a major contributor to neurogenic hypertension. Although overexpression of angiotensin-converting enzyme type 2 (ACE2) has been shown to be beneficial in reducing hypertension by transforming angiotensin II into angiotensin-(1-7), several groups have reported decreased brain ACE2 expression and activity during the development of hypertension.
  
  
  OBJECTIVE
  We hypothesized that ADAM17-mediated ACE2 shedding results in decreased membrane-bound ACE2 in the brain, thus promoting the development of neurogenic hypertension.
  
  
  RESULTS
  To test this hypothesis, we used the deoxycorticosterone acetate-salt model of neurogenic hypertension in nontransgenic and syn-hACE2 mice overexpressing ACE2 in neurons. Deoxycorticosterone acetate-salt treatment in nontransgenic mice led to significant increases in blood pressure, hypothalamic angiotensin II levels, inflammation, impaired baroreflex sensitivity, and autonomic dysfunction, as well as decreased hypothalamic ACE2 activity and expression, although these changes were blunted or prevented in syn-hACE2 mice. In addition, reduction of ACE2 expression and activity in the brain paralleled an increase in ACE2 activity in the cerebrospinal fluid of nontransgenic mice after deoxycorticosterone acetate-salt treatment and were accompanied by enhanced ADAM17 expression and activity in the hypothalamus. Chronic knockdown of ADAM17 in the brain blunted the development of hypertension and restored ACE2 activity and baroreflex function.
  
  
  CONCLUSIONS
  Our data provide the first evidence that ADAM17-mediated shedding impairs brain ACE2 compensatory activity, thus contributing to the development of neurogenic hypertension.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics and Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Huijing
authors.initials: H
authors.lastname: Xia
authors.affiliation: Department of Pharmacology and Experimental Therapeutics and Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Sriramula
authors.affiliation: Department of Pharmacology and Experimental Therapeutics and Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Kavaljit H
authors.initials: KH
authors.lastname: Chhabra
authors.affiliation: Department of Pharmacology and Experimental Therapeutics and Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Lazartigues
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000072198:ADAM17 Protein; D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001341:Autonomic Nervous System / Q000378:metabolism / Q000503:physiopathology; D017704:Baroreflex; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D064791:Desoxycorticosterone Acetate; D004195:Disease Models, Animal; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012084:Renin-Angiotensin System / Q000187:drug effects; D013997:Time Factors
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D000804:Angiotensin II; D064791:Desoxycorticosterone Acetate; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse
keywords: angiotensin; autonomic dysfunction; baroreflex; central nervous system; gene therapy; hypertension; inflammation