(Circulation. 1999;100:654-658.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Chymase-Dependent Angiotensin II Formation in Human Vascular Tissue
From the Department of Pharmacology, Osaka Medical College, Takatsuki City, Osaka, Japan.
Correspondence to Shinji Takai, PhD, Department of Pharmacology, Osaka Medical College, Takatsuki City, Osaka 569-8686, Japan. E-mail Pha010{at}art.osaka-med.ac.jp
Background—Some reports have
suggested that, in vitro, human heart chymase in
homogenates contributes little to angiotensin
(Ang) II formation in the presence of natural protease
inhibitors such as 
-antitrypsin. We studied whether
chymase bound to heparin, resembling an in vivo form, could contribute
to Ang II formation in the presence of natural protease
inhibitors.
Methods and Results—The Ang II formation was increased
time-dependently after incubation in an extract (1 mg of protein/mL) of
human vascular tissues containing Ang I. The concentration of Ang II in
the extract after incubation for 30 minutes was 1.67±0.06 nmol/mL, and
we regarded this quantity of Ang II as 100%. The Ang II formation was
inhibited 10%, 95%, and 96% by 1 µmol/L
lisinopril, 100 µmol/L chymostatin, and 0.1 g/L
-antitrypsin, respectively. The extract was applied to a heparin
affinity column. After the column was washed with PBS, the eluted PBS
contained a weak Ang II-forming activity, which was completely
inhibited by lisinopril. The eluted PBS, to which >0.8
mol/L NaCl had been added, showed a strong Ang II-forming activity
which was inhibited by chymostatin and -antitrypsin. After the
application of the extract, the column was washed with PBS and then an
Ang I solution in PBS was applied to the column. The Ang II formation
in the PBS eluted from the incubated column was increased
time-dependently. The concentration of Ang II in the PBS (1 mL) eluted
from the column after incubation for 30 minutes was 2.56±0.28 nmol/mL,
and we regarded this quantity of Ang II as 100%. To study the effects
of inhibitors, the extract (1 mg of protein/mL) was applied
to a heparin affinity column (1 mL) which was preequilibrated with PBS
(3 mL); 100 µmol/L chymostatin or 0.1 g/L -antitrypsin in PBS
(1 mL) was then applied to the column. After the column was washed with
PBS (3 mL), Ang I solution (1 mg/mL) in PBS was applied to the column,
and the column was incubated for 30 minutes. The Ang II formation in
the PBS eluted from the column was suppressed up to 5% by application
of chymostatin, although this was not affected by application of
-antitrypsin.
Conclusions—These findings suggest that human chymase bound to
heparin plays a functional role in Ang II formation in the presence of
natural protease inhibitors such as -antitrypsin.
Key Words: chymase • angiotensin • heparin • vascular tissue
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