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Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT 84132
Human neutrophils express inducible, catalytically active cathepsin
G on their cell surface. Herein, we report that membrane-bound
cathepsin G on intact neutrophils has potent angiotensin II-generating
activity. Membrane-bound cathepsin G on activated neutrophils 1)
converts both human angiotensin I and angiotensinogen to angiotensin
II; 2) expresses angiotensin II-generating activity equivalent to
8.6 ± 2.3 (±SD) x 10-18 mol of free
cathepsin G (5.2 ± 1.4 x 106 molecules)/cell;
and 3) has similar high affinity for angiotensin I compared with free
cathepsin G (Km = 5.9 x
10-4 and 4.6 x 10-4 M;
kcat = 4.0 and 2.0/s, respectively). In marked
contrast to soluble cathepsin G, membrane-bound enzyme was
substantially resistant to inhibition by plasma proteinase inhibitors
and converted angiotensin I to angiotensin II even in undiluted plasma.
There was a striking inverse relationship between inhibitor size and
its effectiveness against membrane-bound cathepsin G activity.
1-Antichymotrypsin was a markedly ineffective inhibitor
of membrane-bound enzyme (IC50 = 2.18 µM and 1.38 nM when
tested against 1 nM membrane-bound and free cathepsin G, respectively).
These data indicate that membrane-bound cathepsin G expressed on
neutrophils is an inducible and mobile angiotensin II-generating system
that may exert potent local vasoactive and chemoattractant properties
at sites of inflammation.
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