The Ang II (Angiotensin II)-Angiotensin-(1-7) axis of the Renin Angiotensin System encompasses 3 enzymes that form Angiotensin-(1-7) ] directly from Ang II: ACE2 (angiotensin-converting enzyme 2), PRCP (prolylcarboxypeptidase), and POP (prolyloligopeptidase). We investigated their relative contribution to Ang-(1-7) formation in vivo and also ex vivo in serum, lungs, and kidneys using models of genetic ablation coupled with pharmacological inhibitors. In wild-type (WT) mice, infusion of Ang II resulted in a rapid increase of plasma Ang-(1-7). In ACE2 −/− /PRCP −/− mice, Ang II infusion resulted in a similar increase in Ang-(1-7) as in WT (563±48 versus 537±70 fmol/mL, respectively), showing that the bulk of Ang-(1-7) formation in circulation is essentially independent of ACE2 and PRCP. By contrast, a POP inhibitor, Z-Pro-Prolinal reduced the rise in plasma Ang-(1-7) after infusing Ang II to control WT mice. In POP −/− mice, the increase in Ang-(1-7) was also blunted as compared with WT mice (309±46 and 472±28 fmol/mL, respectively P=0.01), and moreover, the rate of recovery from acute Ang II-induced hypertension was delayed (P=0.016). In ex vivo studies, POP inhibition with ZZP reduced Ang-(1-7) formation from Ang II markedly in serum and in lung lysates. By contrast, in kidney lysates, the absence of ACE2, but not POP, obliterated Ang-(1-7) formation from added Ang II. We conclude that POP is the main enzyme responsible for Ang II conversion to Ang-(1-7) in the circulation and in the lungs, whereas Ang-(1-7) formation in the kidney is mainly ACE2-dependent. (Hypertension.

The AngII(1-8)-Ang(1-7) axis of the Renin Angiotensin System (RAS) encompasses three enzymes that form Ang(1-7) directly from AngII: Angiotensin Converting Enzyme 2 (ACE2), Prolyl Carboxypeptidase (PRCP) and Prolyl Endopeptidase (PEP). We studied their relative contribution to Ang(1-7) formation in-vivo and also ex-vivo in serum, lungs and kidneys using models of genetic ablation coupled with pharmacological inhibitors. In WT mice infusion of AngII resulted in a rapid increase of plasma Ang(1-7). In a model of ACE2 and PRCP double genetic ablation AngII infusion resulted in a similar increase in Ang(1-7) as in WT (505 ± 46 vs 482 ± 63 pg/ml, respectively), showing that the bulk of Ang(1-7) formation in circulation is essentially independent of ACE2 and PRCP. By contrast, a PEP inhibitor, ZPP, obliterated the rise in plasma Ang(1-7) after infusing AngII(1-8) to control WT mice. In a genetic mouse model of PEP deficiency (PEP -/- ) the increase in Ang(1-7) was also blunted as compared to WT mice (277±41 and 423±25 pg/ml, respectively p=0.01). The rate of recovery from acute AngII(1-8)-induced hypertension, in PEP -/- mice moreover, was delayed as compared to WT mice (Figure). In ex vivo studies PEP inhibition with ZZP reduced Ang(1-7) formation from Ang(1-8) in serum and in lung lysates. By contrast, in kidney lysates the absence of ACE2, but not PEP, obliterated Ang1-7 formation from added AngII. We conclude that PEP is the main enzyme responsible for AngII conversion to Ang(1-7) in the circulation and in the lungs. PEP, not ACE2, is responsible for protecting against AngII-induced hypertension.