Inhibition of angiotensin-converting enzyme by des-Leu10-angiotensin I: a potential mechanism of endogenous angiotensin-converting enzyme regulation

Snyder, Robert A.; Wintroub, Bruce U.

doi:10.1016/0167-4838(86)90125-1

Cited by 41 publications

(30 citation statements)

References 15 publications

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“…25,26 Ang-(1-9) is a metabolite of ACE2 from angiotensin I and can also be converted to Ang-(1-7) by ACE. 27 Ang-(1-9) has been described previously to potentiate bradykinin release in endothelial cells isolated from cardiac tissue, 16 which may explain the increased NO bioavailability observed in our study. Alternatively, Ang-(1-9) may enhance endothelial NO synthase activation, as has been described for Ang-(1-7).…”

Section: Discussionsupporting

confidence: 60%

Angiotensin-(1-9) Attenuates Cardiac Fibrosis in the Stroke-Prone Spontaneously Hypertensive Rat via the Angiotensin Type 2 Receptor

et al. 2012

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Abstract-The renin-angiotensin system regulates cardiovascular physiology via angiotensin II engaging the angiotensin type 1 or type 2 receptors. Classic actions are type 1 receptor mediated, whereas the type 2 receptor may counteract type 1 receptor activity. Angiotensin-converting enzyme 2 metabolizes angiotensin II to angiotensin-(1-7) and angiotensin I to angiotensin-(1-9). Angiotensin-(1-7) antagonizes angiotensin II actions via the receptor Mas. Angiotensin-(1-9) was shown recently to block cardiomyocyte hypertrophy via the angiotensin type 2 receptor. Here, we investigated in vivo effects of angiotensin-(1-9) via the angiotensin type 2 receptor. Angiotensin-(1-9) (100 ng/kg per minute) with or without the angiotensin type 2 receptor antagonist PD123 319 (100 ng/kg per minute) or PD123 319 alone was infused via osmotic minipump for 4 weeks into stroke-prone spontaneously hypertensive rats. We measured blood pressure by radiotelemetry and cardiac structure and function by echocardiography. Angiotensin-(1-9) did not affect blood pressure or left ventricular mass index but reduced cardiac fibrosis by 50% (PϽ0.01) through modulating collagen I expression, reversed by PD123 319 coinfusion. In addition, angiotensin-(1-9) inhibited fibroblast proliferation in vitro in a PD123 319-sensitive manner. Aortic myography revealed that angiotensin-(1-9) significantly increased contraction to phenylephrine compared with controls after N-nitro-L-arginine methyl ester treatment, an effect abolished by PD123 319 coinfusion (area under the curve: angiotensin-(1-9) N-nitro-L-arginine methyl esterϭ98.9Ϯ11.8%; controlϩN-nitro-Larginine methyl esterϭ74.0Ϯ10.4%; PϽ0.01), suggesting that angiotensin-(1-9) improved basal NO bioavailability in an angiotensin type 2 receptor-sensitive manner. In summary, angiotensin-(1-9) reduced cardiac fibrosis and altered aortic contraction via the angiotensin type 2 receptor supporting a direct role for angiotensin-(1-9) in the reninangiotensin system. (Hypertension. 2012;59:300-307.) • Online Data Supplement Key Words: renin-angiotensin system Ⅲ angiotensin-(1-9) Ⅲ cardiac fibrosis Ⅲ angiotensin type 2 receptor Ⅲ stroke-prone spontaneously hypertensive rat A ngiotensin II (Ang II) is the main effector of the renin-angiotensin system (RAS), classically acting via the angiotensin type 1 receptor (AT 1 R) to stimulate effects such as sodium reabsorption, vasoconstriction, proliferation, and inflammation. Ang II, acting via the AT 1 R, contributes to the pathophysiology of cardiovascular disease. The angiotensin type 2 receptor (AT 2 R) is 34% homologous to the AT 1 R, 1 and its actions differ. 2,3 AT 2 R expression is limited to fetal/neonatal tissues 4 ; however, in adult rodents it is upregulated in heart failure and postmyocardial infarction. 5 In human adult myocardium, 41% of angiotensin binding sites are AT 2 Rs. 5 Ang II signaling via the AT 2 R counteracts AT 1 R signaling; for example, blocking AT 2 R activation promotes cardiomyocyte hypertrophy, 2 whereas AT 2 R overexpression in stroke-p...

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Section: Discussionsupporting

confidence: 60%

Angiotensin-(1-9) Attenuates Cardiac Fibrosis in the Stroke-Prone Spontaneously Hypertensive Rat via the Angiotensin Type 2 Receptor

et al. 2012

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“…These concentrations are over an order of magnitude below the concentration values of the dose that produces 50% inhibition (IC 50 ) of these two peptides. 15,21,25 Consequently, both Ang 1-9 and Ang 1-7 increased the activity of the ACE-resistant B 2 ligand at a concentration that would not inhibit ACE significantly in solution. Furthermore, Ang 1-9 is active per se without being converted to Ang 1-7.…”

Section: Potentiation Of Bradykininmentioning

confidence: 99%

“…23,24 CATA cleaves peptide bonds optimally at acid pH, but esters and amide bonds of C-terminal amino acids at a neutral pH. 19 It was reported that in micromolar concentration, Ang 1-9 inhibits ACE 25,26 and potentiates BK action on its B 2 receptor. 26 Here, we report that CATA is abundantly present in human heart tissues.…”

mentioning

confidence: 99%

Angiotensin 1-9 and 1-7 Release in Human Heart

et al. 2002

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Abstract-Human heart tissue enzymes cleave angiotensin (Ang) I to release Ang 1-9, Ang II, or Ang 1-7. In atrial homogenate preparations, cathepsin A (deamidase) is responsible for 65% of the liberated Ang 1-9. Ang 1-7 was released (88% to 100%) by a metallopeptidase, as established with peptidase inhibitors. Ang II was liberated to about equal degrees by ACE and chymase-type enzymes. Cathepsin A's presence in heart tissue was also proven because it deamidated enkephalinamide substrate by immunoprecipitation of cathepsin A with antiserum to human recombinant enzyme and by immunohistochemistry. In immunohistochemistry, cathepsin A was detected in myocytes of atrial tissue. The products of Ang I cleavage, Ang 1-9 and Ang 1-7, potentiated the effect of an ACE-resistant bradykinin analog and enhanced kinin effect on the B 2 receptor in Chinese hamster ovary cells transfected to express human ACE and B 2 (CHO/AB), and in human pulmonary arterial endothelial cells. Ang 1-9 and 1-7 augmented arachidonic acid and nitric oxide (NO) release by kinin. Direct assay of NO liberation by bradykinin from endothelial cells was potentiated at 10 nmol/L concentration, 2.4-fold (Ang 1-9) and 2.1-fold (Ang 1-7); in higher concentrations, Ang 1-9 was significantly more active than Ang 1-7. Both peptides had traces of activity in the absence of bradykinin. Ang 1-9 and Ang 1-7 potentiated bradykinin action on the B 2 receptor by raising arachidonic acid and NO release at much lower concentrations than their 50% inhibition concentrations (IC 50 s) with ACE.

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“…This enzyme cleaves the His 9 -Leu 10 bond in angiotensin I and as a result generates the fragment angiotensin [1][2][3][4][5][6][7][8][9] , which although capable of inhibiting ACE, has no known intrinsic contractile activity. 26 The human heart has been shown to possess carboxypeptidase A activity, generation of angiotensin [1][2][3][4][5][6][7][8][9] by this enzyme is sufficient to block cardiac ACE. 27 It is undetermined if human blood vessels also exhibit cardoxypeptidase A activity, or if endogenous local ACE activity in the vessel wall is regulated by the synthesis of angiotensin [1][2][3][4][5][6][7][8][9] .…”

Section: Alternative Angiotensin II Generating Enzymesmentioning

confidence: 99%