title: Angiotensin II mediates angiotensin converting enzyme type 2 internalization and degradation through an angiotensin II type I receptor-dependent mechanism.
abstract: Angiotensin-converting enzyme type 2 (ACE2) is a pivotal component of the renin-angiotensin system, promoting the conversion of angiotensin II (Ang-II) to Ang-(1-7). We previously reported that decreased ACE2 expression and activity contributes to the development of Ang-II-mediated hypertension in mice. The present study aimed to investigate the mechanisms involved in ACE2 downregulation during neurogenic hypertension. In ACE2-transfected Neuro-2A cells, Ang-II treatment resulted in a significant attenuation of ACE2 enzymatic activity. Examination of the subcellular localization of ACE2 revealed that Ang-II treatment leads to ACE2 internalization and degradation into lysosomes. These effects were prevented by both the Ang-II type 1 receptor (AT1R) blocker losartan and the lysosomal inhibitor leupeptin. In contrast, in HEK293T cells, which lack endogenous AT1R, Ang-II failed to promote ACE2 internalization. Moreover, this effect could be induced after AT1R transfection. Furthermore, coimmunoprecipitation experiments demonstrated that AT1R and ACE2 form complexes, and these interactions were decreased by Ang-II treatment, which also enhanced ACE2 ubiquitination. In contrast, ACE2 activity was not changed by transfection of AT2 or Mas receptors. In vivo, Ang-II-mediated hypertension was blunted by chronic infusion of leupeptin in wildtype C57Bl/6, but not in ACE2 knockout mice. Overall, this is the first demonstration that elevated Ang-II levels reduce ACE2 expression and activity by stimulation of lysosomal degradation through an AT1R-dependent mechanism.
authors.affiliation: Department of Pharmacology & Experimental Therapeutics and Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Deshotels
authors.affiliation: Department of Pharmacology & Experimental Therapeutics and Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
authors.forename: Huijing
authors.initials: H
authors.lastname: Xia
authors.affiliation: Department of Pharmacology & Experimental Therapeutics and Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Sriramula
authors.affiliation: Department of Pharmacology & Experimental Therapeutics and Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Lazartigues
authors.affiliation: Department of Pharmacology & Experimental Therapeutics and Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, USA.|Department of Pharmacology, College of Medicine, Howard University Washington, DC, USA.
authors.forename: Catalin M
authors.initials: CM
authors.lastname: Filipeanu
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000085962:Angiotensin-Converting Enzyme 2; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D007703:Peptidyl-Dipeptidase A / Q000096:biosynthesis*; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2
keywords: autonomic nervous system; hypertension; proteasome endopeptidase complex; renin-angiotensin system