Bovine Aortic Endothelial Cells Contain an Angiotensin-(1–7) Receptor

Abstract

Anglotensm-(l-7) 1s a novel pepttde of the renlnanglotensm system that counteracts the pressor and prohferatlve responses to anglotensm II We now report that cultured bovme aortlc endothellal cells contam a saturable, high-affinity ['?]anglotensm-(l-7) bmdmg site with an affmlty of 19 3% 10 7 nmol/L and a density of 1351+710 fmol/mg protem Anglotensm-(1-7) competed at a second lower-affimty site, with an IC& of 2 9 PmollL The high-affinity anglotensm II receptor antagonist sarcosmel-lsoleucme*-anglotensm II blocked ["?]anglotensm-(l-7) bmdmg to bovine aortlc endothehal cells at both a high-(ICsO= 1 3 nmol/L) and a low-affimty (I&=6 2 /Imol/L) bmdmg site In contrast, D-alanme'-anglotensm-( l-7) completely blocked ['251]anglotensm-(1-7) bmdmg, with an IC50 of 19 8 nmol/L, suggesting that D-alanme'-anglotensm-( l-7) may selectively block responses to anglotensln-(l-7) In endothehal cellsNeither the AT, antagomst losartan nor the AT2 antagonist PD 123319 exhibited slgmficant competltlon for ['251]anglotensm-(l-7) bmdmg to endothehal cells isolated from bovine aorta, m agreement with the absence of detectable mRNAs encoding typlcal anglotensm receptor subtypes I or 2 (AT, or AT2) Anglotensm II also competed for [ '251]anglotensm-( l-7) bmdmg to bovine aortlc endothehal cell?, however, the relative affinity was 13-fold lower than anglotensm-(l-7), suggestmg a preference for anglotennn-( 1-7) over anglotensm II These results demonstrate that bovi ne aortlc endothehal cells contam a unique non-AT,, non-AT2 anglotensm receptor that preferentially binds anglotensm-( l-7) (Hypertension. 1997;29[part 2]:388-393.) Key Words l angiotensin-(l-7) l angiotemin II l angiotensm receptor subtypes l endothelmm l vascular A ng-( l-7), the N-terminal heptapeptide fragment of Ang II, was identified m the plasma and &sues of animals and humans, at concentrations slmliar to Ang 11 I-6 In addition, clrculatmg levels of Ang-(l-7) increased after treatment of rats, dogs, or humans with ACE inhlbltorsl-6 or hypertensive rats with the AT, antagonist losartan 2 We showed that Ang-(l-7) 1s generated from either Ang 1 or Ang 11 by tissue endopeptldases, including neutral endopeptldase 24 11 (nepnlysm), prolyl endopeptldase, or metallopeptldase 24.15 (thlmet oligopeptldase) 7-11 Thus, Ang-( l-7) is an endogenous component of the remn-anglotensm system, and peptlde levels are significantly elevated after treatment with ACE mhlbltors or ATI receptor antagonists Ang-( l-7) was ongmally consldered an inactive product of Ang 11 metabolism, on the basis of its mablhty to mimic the dipsogemc, vasoconstrlctor, or aldosterone-secretmg actions of Ang II.12 It 1s now known that Ang-(l-7) is a biologically active peptlde hormone having dlstmct and often opposite effects from those of Ang II Ang-( l-7) stimulates the actlvlty of neuropeptlderglc neurons that regulate vasopressm production and transmltter releasel3J4 and releases prostaglandms from astrocytes, smooth muscle cells and vascular endothehal Although the characterlstlcs of an angloten...

Antithrombotic Effect of Captopril and Losartan Is Mediated by Angiotensin-(1-7)

“…This possibility seems likely because similar atypical angiotensin receptors have been described previously. 28,35 Alternatively, an interplay between AT 1 and a putative Ang-(1-7) receptor may be necessary for the antithrombotic action of the peptide to occur. The involvement of AT 1 receptor is in line with studies showing that Ang-(1-7) may either modulate the allosteric binding of Ang II to the AT 1 receptor or compete with Ang II for this binding site.…”

“…The infusion started 10 minutes before the induction of venous thrombosis and was continued for the entire period of thrombus development. To assess whether the potential antithrombotic effect of Ang-(1-7) could be receptor specific, the rats were treated with A-779 (selective Ang- [1][2][3][4][5][6][7] receptor antagonist [27][28][29] D-Ala-Ang- [1][2][3][4][5][6][7]; 100 to 10 000 pmol/kg per minute IV), EXP 3174 (AT 1 receptor antagonist; 1.2 mol/kg IV bolus injection), or PD 123,319 (angiotensin type 2 [AT 2 ] receptor antagonist; 10 nmol/kg per minute IV) 5 minutes before the infusion of Ang-(1-7) (10 pmol/kg per minute) or 0.9% NaCl.…”

Angiotensin‐(1‐7): Pharmacology and New Perspectives in Cardiovascular Treatments

“…However, studies by Tallant et al (1997) showed that Ang-(1-7) bound a non-AT 1 , non-AT 2 receptor with high affinity, which was completely blocked by the addition of the Ang-(1-7) antagonist, D-Ala 7 -Ang-(1-7). It was recently discovered that the orphaned mas oncogene bound Ang-(1-7) with high affinity (Lemos et al 2005).…”

“…Two major questions that need to be addressed are: (1) are the reported effects thus far on Ang-(1-7) due to the activation of the mas receptor, and (2) are the current Ang-(1-7) antagonists solely specific to the mas receptor? Binding studies showed that Ang-(1-7) binds a receptor, which was completely blocked with the addition of D-Ala 7 -Ang-(1-7) (Tallant et al 1997), suggesting involvment of the mas receptor. Therefore, it is known that Ang-(1-7) binds the mas receptor and is a least partially responsible for the physiological effects reported for Ang-(1-7), but given the current data on interactions of the different angiotensin receptors (Castro et al 2005;Kostenis et al 2005), we do not even come close to understanding the roles of the angiotensin receptor types as they pertain to their physiological actions and/or interactions.…”

Angiotensin-(1-7) Through Receptor Mas Mediates Endothelial Nitric Oxide Synthase Activation via Akt-Dependent Pathways

“…13 Previous studies demonstrated that endothelial cells are capable of generating Ang-(1-7) from its precursors Ang I and Ang II because they apparently express the required converting enzymes. 14 Endothelial cells possess Ang-(1-7) receptors, 15 and Ang-(1-7) stimulates NO production in these cells. 16 Recently, our group reported that short-term stimulation of the receptor Mas by Ang-(1-7) improves endothelial function through facilitation of NO release.…”