Evidence for an angiotensin-(1-7) neuropeptidase expressed in the brain medulla and CSF of sheep
© 2014 International Society for Neurochemistry..
Angiotensin-(1-7) [Ang-(1-7)] is an alternative product of the brain renin-angiotensin system that exhibits central actions to lower blood pressure and improve baroreflex sensitivity. We previously identified a peptidase that metabolizes Ang-(1-7) to the inactive metabolite product Ang-(1-4) in CSF of adult sheep. This study purified the peptidase 1445-fold from sheep brain medulla and characterized this activity. The peptidase was sensitive to the chelating agents o-phenanthroline and EDTA, as well as the mercury compound p-chloromercuribenzoic acid (PCMB). Selective inhibitors to angiotensin-converting enzyme, neprilysin, neurolysin, and thimet oligopeptidase did not attenuate activity; however, the metallopeptidase agent JMV-390 was a potent inhibitor of Ang-(1-7) hydrolysis (Ki = 0.8 nM). Kinetic studies using (125) I-labeled Ang-(1-7), Ang II, and Ang I revealed comparable apparent Km values (2.6, 2.8, and 4.3 μM, respectively), but a higher apparent Vmax for Ang-(1-7) (72 vs. 30 and 6 nmol/min/mg, respectively; p < 0.01). HPLC analysis of the activity confirmed the processing of unlabeled Ang-(1-7) to Ang-(1-4) by the peptidase, but revealed < 5% hydrolysis of Ang II or Ang I, and no hydrolysis of neurotensin, bradykinin or apelin-13. The unique characteristics of the purified neuropeptidase may portend a novel pathway to influence actions of Ang-(1-7) within the brain. Angiotensin-(1-7) actions are mediated by the AT7 /Mas receptor and include reduced blood pressure, decreased oxidative stress, enhanced baroreflex sensitivity, and increased nitric oxide (NO). Ang-(1-7) is directly formed from Ang I by neprilysin (NEP). We identify a new pathway for Ang-(1-7) metabolism in the brain distinct from angiotensin-converting enzyme-dependent hydrolysis. The Ang-(1-7) endopeptidase (A7-EP) degrades the peptide to Ang-(1-4) and may influence central Ang-(1-7) tone.
Medienart: |
E-Artikel |
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Erscheinungsjahr: |
2014 |
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Erschienen: |
2014 |
Enthalten in: |
Zur Gesamtaufnahme - volume:130 |
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Enthalten in: |
Journal of neurochemistry - 130(2014), 2 vom: 07. Juli, Seite 313-23 |
Sprache: |
Englisch |
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Beteiligte Personen: |
Marshall, Allyson C [VerfasserIn] |
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Links: |
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Anmerkungen: |
Date Completed 10.09.2014 Date Revised 21.10.2021 published: Print-Electronic Citation Status MEDLINE |
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doi: |
10.1111/jnc.12720 |
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funding: |
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Förderinstitution / Projekttitel: |
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PPN (Katalog-ID): |
NLM236684787 |
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245 | 1 | 0 | |a Evidence for an angiotensin-(1-7) neuropeptidase expressed in the brain medulla and CSF of sheep |
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520 | |a Angiotensin-(1-7) [Ang-(1-7)] is an alternative product of the brain renin-angiotensin system that exhibits central actions to lower blood pressure and improve baroreflex sensitivity. We previously identified a peptidase that metabolizes Ang-(1-7) to the inactive metabolite product Ang-(1-4) in CSF of adult sheep. This study purified the peptidase 1445-fold from sheep brain medulla and characterized this activity. The peptidase was sensitive to the chelating agents o-phenanthroline and EDTA, as well as the mercury compound p-chloromercuribenzoic acid (PCMB). Selective inhibitors to angiotensin-converting enzyme, neprilysin, neurolysin, and thimet oligopeptidase did not attenuate activity; however, the metallopeptidase agent JMV-390 was a potent inhibitor of Ang-(1-7) hydrolysis (Ki = 0.8 nM). Kinetic studies using (125) I-labeled Ang-(1-7), Ang II, and Ang I revealed comparable apparent Km values (2.6, 2.8, and 4.3 μM, respectively), but a higher apparent Vmax for Ang-(1-7) (72 vs. 30 and 6 nmol/min/mg, respectively; p < 0.01). HPLC analysis of the activity confirmed the processing of unlabeled Ang-(1-7) to Ang-(1-4) by the peptidase, but revealed < 5% hydrolysis of Ang II or Ang I, and no hydrolysis of neurotensin, bradykinin or apelin-13. The unique characteristics of the purified neuropeptidase may portend a novel pathway to influence actions of Ang-(1-7) within the brain. Angiotensin-(1-7) actions are mediated by the AT7 /Mas receptor and include reduced blood pressure, decreased oxidative stress, enhanced baroreflex sensitivity, and increased nitric oxide (NO). Ang-(1-7) is directly formed from Ang I by neprilysin (NEP). We identify a new pathway for Ang-(1-7) metabolism in the brain distinct from angiotensin-converting enzyme-dependent hydrolysis. The Ang-(1-7) endopeptidase (A7-EP) degrades the peptide to Ang-(1-4) and may influence central Ang-(1-7) tone | ||
650 | 4 | |a Journal Article | |
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650 | 4 | |a Research Support, Non-U.S. Gov't | |
650 | 4 | |a Ang-(1-7) | |
650 | 4 | |a Renin-angiotensin system | |
650 | 4 | |a metabolism | |
650 | 4 | |a neuropeptidase | |
650 | 7 | |a Intercellular Signaling Peptides and Proteins |2 NLM | |
650 | 7 | |a Mercury Compounds |2 NLM | |
650 | 7 | |a Oligopeptides |2 NLM | |
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650 | 7 | |a Bradykinin |2 NLM | |
650 | 7 | |a S8TIM42R2W |2 NLM | |
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700 | 1 | |a Rose, James C |e verfasserin |4 aut | |
700 | 1 | |a Diz, Debra I |e verfasserin |4 aut | |
700 | 1 | |a Chappell, Mark C |e verfasserin |4 aut | |
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