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Aims:  Apelin is a predicted substrate for ACE2, a novel therapeutic target. Our aim was to demonstrate the endogenous presence of the putative ACE2 product [Pyr 1 ]apelin-13 (1–12)  in human cardiovascular tissues and to confirm it retains significant biological activity for the apelin receptor  in vitro  and  in vivo . The minimum active apelin fragment was also investigated.   Methods and Results:  [Pyr 1 ]apelin-13 incubated with recombinant human ACE2 resulted in de novo generation of [Pyr 1 ]apelin-13 (1–12)  identified by mass spectrometry. Endogenous [Pyr 1 ]apelin-13 (1–12)  was detected by immunostaining in human heart and lung localized to the endothelium. Expression was undetectable in lung from patients with pulmonary arterial hypertension. In human heart [Pyr 1 ]apelin-13 (1–12)  (pK i  = 8.04 ± 0.06) and apelin-13(F13A) (pK i  = 8.07 ± 0.24) competed with [ 125 I]apelin-13 binding with nanomolar affinity, 4-fold lower than for [Pyr 1 ]apelin-13 (pK i  = 8.83 ± 0.06) whereas apelin-17 exhibited highest affinity (pK i  = 9.63 ± 0.17). The rank order of potency of peptides to inhibit forskolin-stimulated cAMP was apelin-17 (pD 2  = 10.31 ± 0.28) > [Pyr 1 ]apelin-13 (pD 2  = 9.67 ± 0.04) ≥ apelin-13(F13A) (pD 2  = 9.54 ± 0.05) > [Pyr 1 ]apelin-13 (1–12)  (pD 2  = 9.30 ± 0.06). The truncated peptide apelin-13(R10M) retained nanomolar potency (pD 2  = 8.70 ± 0.04) but shorter fragments exhibited low micromolar potency. In a β-arrestin recruitment assay the rank order of potency was apelin-17 (pD 2  = 10.26 ± 0.09) >> [Pyr 1 ]apelin-13 (pD 2  = 8.43 ± 0.08) > apelin-13(R10M) (pD 2  = 8.26 ± 0.17) > apelin-13(F13A) (pD 2  = 7.98 ± 0.04) ≥ [Pyr 1 ]apelin-13 (1–12)  (pD 2  = 7.84 ± 0.06) >> shorter fragments (pD 2  < 6). [Pyr 1 ]apelin-13 (1–12)  and apelin-13(F13A) contracted human saphenous vein with similar sub-nanomolar potencies and [Pyr 1 ]apelin-13 (1–12)  was a potent inotrope in paced mouse right ventricle and human atria. [Pyr 1 ]apelin-13 (1–12)  elicited a dose-dependent decrease in blood pressure in anesthetized rat and dose-dependent increase in forearm blood flow in human volunteers.   Conclusions:  We provide evidence that ACE2 cleaves [Pyr 1 ]apelin-13 to [Pyr 1 ]apelin-13 (1–12)  and this cleavage product is expressed in human cardiovascular tissues. We have demonstrated biological activity of [Pyr 1 ]apelin-13 (1–12)  at the human and rodent apelin receptor  in vitro  and  in vivo . Our data show that reported enhanced ACE2 activity in cardiovascular disease should not significantly compromise the beneficial effects of apelin based therapies for example in PAH.

[Pyr1]Apelin-13(1–12) Is a Biologically Active ACE2 Metabolite of the Endogenous Cardiovascular Peptide [Pyr1]Apelin-13