Key result
Human plasma proteins process Angiotensin-I into ANG-2-10, ANG-3-10, ANG-4-10, ANG-5-10, and ANG-6-10 via an aminopeptidase-mediated pathway, bypassing the known carboxypeptidase pathway.
This study demonstrates the existence of an aminopeptidase-mediated pathway in humans that processes ANG-1-10 into smaller peptides, expanding the current understanding of the human renin-angiotensin system.
Identifies aminopeptidase Ang-I processing in human plasma; leaves open clinical relevance and requires in vivo validation.
In mammalian species, except humans, N-terminal processing of the precursor peptide angiotensin I (ANG-1-10) into ANG-2-10 or ANG-3-10 was reported. Here we hypothesize that aminopeptidase-generated angiotensins bearing the same C-terminus as ANG-1-10 are also present in humans. We demonstrate the time dependent generation of ANG-2-10, ANG-3-10, ANG-4-10, ANG-5-10 and ANG-6-10 from the precursor ANG-1-10 by human plasma proteins. The endogenous presence of ANG-4-10, ANG-5-10 and ANG-6-10 in human plasma was confirmed by an immuno-fluorescence assay. Generation of ANG-2-10, ANG-3-10 and ANG-4-10 from ANG-1-10 by immobilized human plasma proteins was sensitive to the cysteine/serine protease inhibitor antipain. The metal ion chelator EDTA inhibited Ang-6-10-generation. Incubation of the substrates ANG-3-10, ANG-4-10 and ANG-5-10 with recombinant aminopeptidase N (APN) resulted in a successive N-terminal processing, finally releasing ANG-6-10 as a stable end product, demonstrating a high similarity concerning the processing pattern of the angiotensin peptides compared to the angiotensin generating activity in plasma. Recombinant ACE-1 hydrolyzed the peptides ANG-2-10, ANG-3-10, ANG-4-10 and ANG-5-10 into ANG-2-8, ANG-3-8, ANG-4-8 and ANG-5-8. Since ANG-2-10 was processed into ANG-2-8, ANG-4-8 and ANG-5-8 by plasma proteases the angiotensin peptides bearing the same C-terminus as ANG-1-10 likely have a precursor function in human plasma. Our results confirm the hypothesis of aminopeptidase mediated processing of ANG-1-10 in humans. We show the existence of an aminopeptidase mediated pathway in humans that bypasses the known ANG-1-8-carboxypeptidase pathway. This expands the knowledge about the known human renin angiotensin system, showing how efficiently the precursor ANG-1-10 is used by nature.
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Hildebrand et al. (2013) studied Healthy (n=2). In vitro incubation of Angiotensin-I with human plasma proteins vs. Control samples without active plasma proteins was evaluated on Time-dependent generation of ANG-2-10, ANG-3-10, ANG-4-10, ANG-5-10 and ANG-6-10. Human plasma proteins process Angiotensin-I into ANG-2-10, ANG-3-10, ANG-4-10, ANG-5-10, and ANG-6-10 via an aminopeptidase-mediated pathway, bypassing the known carboxypeptidase pathway.
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