Ang II (Angiotensin II) Conversion to Angiotensin-(1-7) in the Circulation Is POP (Prolyloligopeptidase)-Dependent and ACE2 (Angiotensin-Converting Enzyme 2)-Independent

Abstract

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.

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“…The latter acts as a vasodilator and has anti-inflammatory and cardioprotective effects. According to animal studies, expression of ACE2 in lung tissues is low under normal conditions [31], but is upregulated during lung injury [32]. In fact, some animal studies [33] and pilot studies in humans [34] have suggested a potential therapeutic role of ACE2 against inflammatory acute lung injury.…”

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“…This is not surprising, since ACE2 and ACE are different enzymes, and ACE inhibitors have been designed specifically for ACE only. ACE2 is a membranebound enzyme, with very low (soluble) levels in blood [8,9]. The occurrence of sACE2 depends on cleavage of its membrane-anchor by A Disintegrin And Metalloprotease 17 (ADAM17) ( Fig.…”

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“…The kidney has abundant ACE2 in the apical border of the proximal tubule where it colocalizes with ACE(9). The lungs, by contrast, have a low level of ACE2 expression such that the metabolism of angiotensin II and formation of angiotensin 1-7 depends on enzymes other than ACE2, namely POP (25). To determine whether deficiency of kidney ACE alters kidney ACE2 expression we used two different genetic models of ACE ablation.…”