Angiotensin 1-9 and 1-7 release in human heart -: Role of cathepsin A

Human heart tissue enzymes cleave angiotensin (Ang) I to release Ang 1-9, Ang II, or Ang 1-7. In atrial homogenate preparations. cathepsin A (deamidase) is responsible for 65% of the liberated Ang 1-9. Ang 1-7 was released (88% to 100%) by a metallopeptidase. as established with peptidase inhibitors. Ang 11 was liberated to about equal degrees by ACE and chymase-type enzymes. Cathepsin A's presence in heart tissue was also proven because it deamidated enkephalinamide substrate by immunoprecipitation of cathepsin A with antiserum to human recombinant enzyme and by immunohistochemistry. In cathepsin A was detected in myocytes of atrial tissue. The products of Ang I cleavage. Ang 1-9 and Ang 1-7. potentiated the effect of an ACE-resistant bradykinin analog and enhanced kinin effect on the B-2 receptor in Chinese hamster ovary cells transfected to express human ACE and B-2 (CHO/AB), and ill human pulmonary arterial endothelial cells. Ang 1-9 and 1-7 augmented arachidonic acid and nitric oxide (NO) release by kinin. Direct assay of NO liberation by brad kinin from endothelial cells was potentiated at 10 nmol/L concentration. 2.4-fold (Ang 1-9) and 2.1-fold (Ang 1-7): in higher concentrations. Ang 1-9 was significantly more active than Ana 1-7. Both peptides had traces of activity in the absence of bradykinin, Ang 1-9 and Ang 1-7 potentiated bradykinin action on the B-2 receptor by raising arachidonic acid and NO release at much lower concentrations than their 50% inhibition concentrations (IC(50)s) with ACE. They probably induce conformational changes in the ACE/B-2 receptor complex via interaction with ACE.