New perspectives in the renin-angiotensin-aldosterone system (RAAS) I: endogenous angiotensin converting enzyme (ACE) inhibition.

Angiotensin-converting enzyme (ACE) inhibitors represent the fifth most often prescribed drugs. ACE inhibitors decrease 5-year mortality by approximately one-fifth in cardiovascular patients. Surprisingly, there are reports dating back to 1979 suggesting the existence of endogenous ACE inhibitors, w...

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Autores principales:	Miklós Fagyas, Katalin Úri, Ivetta M Siket, Andrea Daragó, Judit Boczán, Emese Bányai, István Édes, Zoltán Papp, Attila Tóth
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/19af8274ee3c489ab833304eb12e74fd
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spelling	oai:doaj.org-article:19af8274ee3c489ab833304eb12e74fd2021-11-18T08:25:30ZNew perspectives in the renin-angiotensin-aldosterone system (RAAS) I: endogenous angiotensin converting enzyme (ACE) inhibition.1932-620310.1371/journal.pone.0087843https://doaj.org/article/19af8274ee3c489ab833304eb12e74fd2014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24691160/?tool=EBIhttps://doaj.org/toc/1932-6203Angiotensin-converting enzyme (ACE) inhibitors represent the fifth most often prescribed drugs. ACE inhibitors decrease 5-year mortality by approximately one-fifth in cardiovascular patients. Surprisingly, there are reports dating back to 1979 suggesting the existence of endogenous ACE inhibitors, which endogenous inhibitory effects are much less characterized than that for the clinically administered ACE inhibitors. Here we aimed to investigate this endogenous ACE inhibition in human sera. It was hypothesized that ACE activity is masked by an endogenous inhibitor, which dissociates from the ACE when its concentration decreases upon dilution. ACE activity was measured by FAPGG hydrolysis first. The specific (dilution corrected) enzyme activities significantly increased by dilution of human serum samples (23.2 ± 0.7 U/L at 4-fold dilution, 51.4 ± 0.3 U/L at 32-fold dilution, n = 3, p = 0.001), suggesting the presence of an endogenous inhibitor. In accordance, specific enzyme activities did not changed by dilution when purified renal ACE was used, where no endogenous inhibitor was present (655 ± 145 U/L, 605 ± 42 U/L, n = 3, p = 0.715, respectively). FAPGG conversion strongly correlated with angiotensin I conversion suggesting that this feature is not related to the artificial substrate. Serum samples were ultra-filtered to separate ACE (MW: 180 kDa) and the hypothesized inhibitor. Filtering through 50 kDa filters was without effect, while filtering through 100 kDa filters eliminated the inhibiting factor (ACE activity after <100 kDa filtering: 56.4 ± 2.4 U/L, n = 4, control: 26.4 ± 0.7 U/L, n = 4, p<0.001). Lineweaver-Burk plot indicated non-competitive inhibition of ACE by this endogenous factor. The endogenous inhibitor had higher potency on the C-terminal active site than N-terminal active site of ACE. Finally, this endogenous ACE inhibition was also present in mouse, donkey, goat, bovine sera besides men (increasing of specific ACE activity from 4-fold to 32-fold dilution: 2.8-fold, 1.7-fold, 1.5-fold, 1.8-fold, 2.6-fold, respectively). We report here the existence of an evolutionary conserved mechanism suppressing circulating ACE activity, in vivo, similarly to ACE inhibitory drugs.Miklós FagyasKatalin ÚriIvetta M SiketAndrea DaragóJudit BoczánEmese BányaiIstván ÉdesZoltán PappAttila TóthPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 4, p e87843 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Miklós Fagyas Katalin Úri Ivetta M Siket Andrea Daragó Judit Boczán Emese Bányai István Édes Zoltán Papp Attila Tóth New perspectives in the renin-angiotensin-aldosterone system (RAAS) I: endogenous angiotensin converting enzyme (ACE) inhibition.
description	Angiotensin-converting enzyme (ACE) inhibitors represent the fifth most often prescribed drugs. ACE inhibitors decrease 5-year mortality by approximately one-fifth in cardiovascular patients. Surprisingly, there are reports dating back to 1979 suggesting the existence of endogenous ACE inhibitors, which endogenous inhibitory effects are much less characterized than that for the clinically administered ACE inhibitors. Here we aimed to investigate this endogenous ACE inhibition in human sera. It was hypothesized that ACE activity is masked by an endogenous inhibitor, which dissociates from the ACE when its concentration decreases upon dilution. ACE activity was measured by FAPGG hydrolysis first. The specific (dilution corrected) enzyme activities significantly increased by dilution of human serum samples (23.2 ± 0.7 U/L at 4-fold dilution, 51.4 ± 0.3 U/L at 32-fold dilution, n = 3, p = 0.001), suggesting the presence of an endogenous inhibitor. In accordance, specific enzyme activities did not changed by dilution when purified renal ACE was used, where no endogenous inhibitor was present (655 ± 145 U/L, 605 ± 42 U/L, n = 3, p = 0.715, respectively). FAPGG conversion strongly correlated with angiotensin I conversion suggesting that this feature is not related to the artificial substrate. Serum samples were ultra-filtered to separate ACE (MW: 180 kDa) and the hypothesized inhibitor. Filtering through 50 kDa filters was without effect, while filtering through 100 kDa filters eliminated the inhibiting factor (ACE activity after <100 kDa filtering: 56.4 ± 2.4 U/L, n = 4, control: 26.4 ± 0.7 U/L, n = 4, p<0.001). Lineweaver-Burk plot indicated non-competitive inhibition of ACE by this endogenous factor. The endogenous inhibitor had higher potency on the C-terminal active site than N-terminal active site of ACE. Finally, this endogenous ACE inhibition was also present in mouse, donkey, goat, bovine sera besides men (increasing of specific ACE activity from 4-fold to 32-fold dilution: 2.8-fold, 1.7-fold, 1.5-fold, 1.8-fold, 2.6-fold, respectively). We report here the existence of an evolutionary conserved mechanism suppressing circulating ACE activity, in vivo, similarly to ACE inhibitory drugs.
format	article
author	Miklós Fagyas Katalin Úri Ivetta M Siket Andrea Daragó Judit Boczán Emese Bányai István Édes Zoltán Papp Attila Tóth
author_facet	Miklós Fagyas Katalin Úri Ivetta M Siket Andrea Daragó Judit Boczán Emese Bányai István Édes Zoltán Papp Attila Tóth
author_sort	Miklós Fagyas
title	New perspectives in the renin-angiotensin-aldosterone system (RAAS) I: endogenous angiotensin converting enzyme (ACE) inhibition.
title_short	New perspectives in the renin-angiotensin-aldosterone system (RAAS) I: endogenous angiotensin converting enzyme (ACE) inhibition.
title_full	New perspectives in the renin-angiotensin-aldosterone system (RAAS) I: endogenous angiotensin converting enzyme (ACE) inhibition.
title_fullStr	New perspectives in the renin-angiotensin-aldosterone system (RAAS) I: endogenous angiotensin converting enzyme (ACE) inhibition.
title_full_unstemmed	New perspectives in the renin-angiotensin-aldosterone system (RAAS) I: endogenous angiotensin converting enzyme (ACE) inhibition.
title_sort	new perspectives in the renin-angiotensin-aldosterone system (raas) i: endogenous angiotensin converting enzyme (ace) inhibition.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/19af8274ee3c489ab833304eb12e74fd
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New perspectives in the renin-angiotensin-aldosterone system (RAAS) I: endogenous angiotensin converting enzyme (ACE) inhibition.

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