The Ang II (Angiotensin II)-Angiotensin-(1-7) axis of the Renin Angiotensin System encompasses 3 enzymes that form Angiotensin-(1-7) [Ang-(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.

BACKGROUND AND PURPOSE: The aggregation of α‐synuclein is connected to the pathology of Parkinson's disease and prolyl oligopeptidase (PREP) accelerates the aggregation of α‐synucleinin vitro. The aim of this study was to investigate the effects of a PREP inhibitor, KYP‐2047, on α‐synuclein aggregation in cell lines overexpressing wild‐type or A30P/A53T mutant human α‐syn and in the brains of two A30P α‐synuclein transgenic mouse strains.EXPERIMENTAL APPROACH: Cells were exposed to oxidative stress and then incubated with the PREP inhibitor during or after the stress. Wild‐type or transgenic mice were treated for 5 days with KYP‐2047 (2 × 3 mg·kg⁻¹a day). Besides immunohistochemistry and thioflavin S staining, soluble and insoluble α‐synuclein protein levels were measured by Western blot. α‐synuclein mRNA levels were quantified by PCR. The colocalization of PREP and α‐synuclein,and the effect of KYP‐2047 on cell viability were also investigated.KEY RESULTS: In cell lines, oxidative stress induced a robust aggregation of α‐synuclein,and low concentrations of KYP‐2047 significantly reduced the number of cells with α‐synuclein inclusions while abolishing the colocalization of α‐synuclein and PREP. KYP‐2047 significantly reduced the amount of aggregated α‐synuclein,and it had beneficial effects on cell viability. In the transgenic mice, a 5‐day treatment with the PREP inhibitor reduced the amount of α‐synuclein immunoreactivity and soluble α‐synuclein protein in the brain.CONCLUSIONS AND IMPLICATIONS: The results suggest that the PREP may play a role in brain accumulation and aggregation of α‐synuclein, while KYP‐2047 seems to effectively prevent these processes.