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Greater Angiotensin II Metabolism in Rodents Compared to Humans: Role of Aspartyl and Dipeptidyl Aminopeptidases
Author(s) -
Chappell Mark C.,
Pirro Nancy T.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.00108
Subject(s) - endocrinology , medicine , metabolism , angiotensin ii , renin–angiotensin system , angiotensin ii receptor type 1 , chemistry , angiotensin converting enzyme , angiotensin iii , receptor , enzyme , blockade , biology , biochemistry , blood pressure
Functional tone of the renin‐angiotensin system (RAS) is influenced by the balance of Angiotensin II (Ang II) generation and metabolism. The major if not sole Ang II‐forming enzyme is ACE while amino (AP)‐, endo (EP)‐ and carboxy (CP)‐peptidases degrade Ang II. Rodents are the primary models for Ang II‐evoked hypertension, inflammation and fibrosis, and genetic hypertensive models typically overexpress various RAS components that stimulate the ACE‐Ang II‐AT1 receptor axis. The present study compared Ang II degradation and generation pathways in humans and rodents. We hypothesize that significant species differences regarding Ang II metabolism may exist among humans and rodents. Results Rate of Ang II metabolism in serum (5.0 μl at 37°C for 4 hours) was 9‐fold higher in Sprague‐Dawley rats and 2‐fold higher in C5Bl/6 mice than humans (Fig. 1A). In rats, Ang II metabolism was AP‐dependent forming Ang‐(2‐8), Ang‐(3‐8) and Ang‐(4‐8). AP inhibitors bestatin and amastatin (10 μM each) abolished Ang‐(3‐8) and Ang‐(4‐8), but increased Ang‐(2‐8). Cystiene peptidase inhibition (PCMB) blocked Ang‐(2‐8) generation that distinguished Aspartyl‐AP (Asp‐AP) from Glutamyl‐AP (Glu‐AP) in serum. Complete AP blockade abolished Ang II metabolism in rats. In mice, Ang II metabolism was primarily mediated by a dipeptidyl‐AP(DAP) and to a lesser extent by Asp‐AP and Glu‐AP following DAP blockade. Ang II generation was 2–3‐fold higher in mice than rats and humans (Fig. 1B). Finally, there was no evidence of Ang‐(1‐7) formation from Ang I or Ang II in the serum of all three species. Conclusion To our knowledge, this is the first study that established marked differences in Ang II metabolism between humans and rodents that reflects substantially higher Asp‐AP in rats and greater DAP‐3 in mice. The greater AP and DAP activities may constitute a cardioprotective mechanism particularly in the rat, although additional studies are required to determine whether other tissue compartments express such dramatic differences in AP activity and Ang II metabolism. Support or Funding Information AHA Transformative Grant 18TPA34170522, AHA 14GRNT20480131; NIH 1R01HL146818, NIH HD‐084227;Ang II metabolism (A) and Ang II formation (B) in rat, mouse and human serum. *P<0.05; n=3 determinations from a pool of 10 each.