Angiotensin 1-9 and 1-7 Release in Human Heart: Role of Cathepsin A

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2002-05, Vol.39 (5), p.976-981
• Main Authors: Jackman, Herbert L, Massad, Malek G, Sekosan, Marin, Tan, Fulong, Brovkovych, Viktor, Marcic, Branislav M, Erdös, Ervin G
• Format: Article
• Language: English
• Subjects: Angiotensin I - chemistry; Angiotensin I - drug effects; Angiotensin I - metabolism; Animals; Arachidonic Acid - metabolism; Biological and medical sciences; Bradykinin - analogs & derivatives; Bradykinin - pharmacology; Carboxypeptidases - metabolism; Cathepsin A; Cells, Cultured; CHO Cells; Cricetinae; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Enkephalin, Leucine-2-Alanine - analogs & derivatives; Enkephalin, Leucine-2-Alanine - metabolism; Enkephalins - metabolism; Fundamental and applied biological sciences. Psychology; Heart; Heart Atria - drug effects; Heart Atria - metabolism; Humans; Hydrogen-Ion Concentration; Immunohistochemistry; Myocardium - metabolism; Nitric Oxide - metabolism; Peptide Fragments - metabolism; Peptide Fragments - pharmacology; Peptide Hydrolases - metabolism; Vertebrates: cardiovascular system
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/01.HYP.0000017283.67962.02

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.