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(Hypertension. 2002;39:976.)
© 2002 American Heart Association, Inc.

Scientific Contributions

Angiotensin 1-9 and 1-7 Release in Human Heart

Role of Cathepsin A

Herbert L. Jackman; Malek G. Massad; Marin Sekosan; Fulong Tan; Viktor Brovkovych; Branislav M. Marcic; Ervin G. Erdös

From the Departments of Pharmacology (H.L.J., F.T., V.B., B.M.M., E.G.E.), Surgery (M.G.M.), Pathology (M.S.), and Anesthesiology (F.T., E.G.E.), University of Illinois College of Medicine at Chicago.

Correspondence to Ervin G. Erdös, MD, Dept. of Pharmacology (M/C 868), University of Illinois-Chicago, 835 S. Wolcott Ave., Chicago, IL 60612. E-mail egerdos{at}uic.edu

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 II 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 immunohistochemistry, 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 B₂ receptor in Chinese hamster ovary cells transfected to express human ACE and B₂ (CHO/AB), and in 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 bradykinin 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 Ang 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 B₂ receptor by raising arachidonic acid and NO release at much lower concentrations than their 50% inhibition concentrations (IC₅₀s) with ACE. They probably induce conformational changes in the ACE/B₂ receptor complex via interaction with ACE.

Key Words: peptides • angiotensin-converting enzyme • receptors, bradykinin • nitric oxide

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