title: Angiotensin II binding to angiotensin I-converting enzyme triggers calcium signaling.
abstract: Angiotensin (Ang) I-converting enzyme (ACE) is involved in the control of blood pressure by catalyzing the conversion of Ang I into the vasoconstrictor Ang II and degrading the vasodilator peptide bradykinin. Human ACE also functions as a signal transduction molecule, and the binding of ACE substrates or its inhibitors initiates a series of events. In this study, we examined whether Ang II could bind to ACE generating calcium signaling. Chinese hamster ovary cells transfected with an ACE expression vector reveal that Ang II is able to bind with high affinity to ACE in the absence of the Ang II type 1 and type 2 receptors and to activate intracellular signaling pathways, such as inositol 1,4,5-trisphosphate and calcium. These effects could be blocked by the ACE inhibitor, lisinopril. Calcium mobilization was specific for Ang II, because other ACE substrates or products, namely Ang 1-7, bradykinin, bradykinin 1-5, and N-acetyl-seryl-aspartyl-lysyl-proline, did not trigger this signaling pathway. Moreover, in Tm5, a mouse melanoma cell line endogenously expressing ACE but not Ang II type 1 or type 2 receptors, Ang II increased intracellular calcium and reactive oxygen species. In conclusion, we describe for the first time that Ang II can interact with ACE and evoke calcium and other signaling molecules in cells expressing only ACE. These findings uncover a new mechanism of Ang II action and have implications for the understanding of the renin-Ang system.
authors.affiliation: Departamento de Biofísica, Universidade Federal de São Paulo, Rua Botucatu 862, CEP 04023-062, São Paulo, Brazil.
authors.forename: Paola B
authors.initials: PB
authors.lastname: Guimarães
authors.forename: Érika C
authors.initials: ÉC
authors.lastname: Alvarenga
authors.forename: Paula D
authors.initials: PD
authors.lastname: Siqueira
authors.forename: Edgar J
authors.initials: EJ
authors.lastname: Paredes-Gamero
authors.forename: Regiane A
authors.initials: RA
authors.lastname: Sabatini
authors.forename: Rafael L T
authors.initials: RL
authors.lastname: Morais
authors.forename: Rosana I
authors.initials: RI
authors.lastname: Reis
authors.forename: Edson L
authors.initials: EL
authors.lastname: Santos
authors.forename: Luis G D
authors.initials: LG
authors.lastname: Teixeira
authors.forename: Dulce E
authors.initials: DE
authors.lastname: Casarini
authors.forename: Renan P
authors.initials: RP
authors.lastname: Martin
authors.forename: Suma I
authors.initials: SI
authors.lastname: Shimuta
authors.forename: Adriana K
authors.initials: AK
authors.lastname: Carmona
authors.forename: Clovis R
authors.initials: CR
authors.lastname: Nakaie
authors.forename: Miriam G
authors.initials: MG
authors.lastname: Jasiulionis
authors.forename: Alice T
authors.initials: AT
authors.lastname: Ferreira
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Pesquero
authors.forename: Suzana M
authors.initials: SM
authors.lastname: Oliveira
authors.forename: Michael
authors.initials: M
authors.lastname: Bader
authors.forename: Claudio M
authors.initials: CM
authors.lastname: Costa-Neto
authors.forename: João B
authors.initials: JB
authors.lastname: Pesquero
mesh_terms: D000704:Analysis of Variance; D000804:Angiotensin II / Q000378:metabolism*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D005434:Flow Cytometry; D017706:Lisinopril / Q000494:pharmacology; D051379:Mice; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D017382:Reactive Oxygen Species; D000804:Angiotensin II; D017706:Lisinopril; D007703:Peptidyl-Dipeptidase A