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

Abstract

Abstract-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 B 2 receptor in Chinese hamster ovary cells transfected to express human ACE and B 2 (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 B 2 receptor by raising arachidonic acid and NO release at much lower concentrations than their 50% inhibition concentrations (IC 50 s) with ACE.

Angiotensin-(1-9) Attenuates Cardiac Fibrosis in the Stroke-Prone Spontaneously Hypertensive Rat via the Angiotensin Type 2 Receptor

“…15 Ang-(1-9) is thought to reduce Ang II levels because it competes with angiotensin I at the ACE active site and increases Ang-(1-7) and stimulates bradykinin release in endothelial cells. 16 Recently Ang-(1-9) was demonstrated to inhibit cardiac hypertrophy after myocardial infarction in rats. 17 This was not dependent on Ang-(1-9) to Ang-(1-7) conversion, because coadministration of the Mas antagonist A779 did not influence the effects of Ang-(1-9).…”

New Components of the Renin-Angiotensin-Aldosterone System and Oxidative Stress

“…Less Ang-(1-7) is produced from Ang-(1-9) by ACE and other alternative enzymes such as prolyl endopeptidase, neutral endopeptidase, or thimet oligopeptidase [27,28]. Ang-(1-9) is produced from AngⅠ by ACE2, carboxypeptidase A or cathepsin A [29,30]. Ang-(1-7) is endogenous ligand for G protein-coupled receptor (GPCR) Mas [31], eliciting antagonistic reaction against AT 1 receptor including vasodilation, antiproliferation in the vasculature, antihypertrophy, antifibrosis, antiarrythmia in the heart, and many other protective reactions in the kidney, and the brain etc [32].…”

Angiotensin-(1–9) enhances stasis-induced venous thrombosis in the rat because of the impairment of fibrinolysis

“…In vitro Ang-(1-9) is a potent competitive inhibitor of ACE 6 and a stimulator of NO release. 19 However, Ang-(1-9), similarly to Ang II, increases nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. 12 This effect could be responsible for the accumulation of reactive oxygen species, which in turn could enhance adhesion of leukocytes to the endothelial surface.…”