© 1998 American Heart Association, Inc.
Original Contributions |
Possible Involvement of m-Calpain in Vascular Smooth Muscle Cell Proliferation
From the Second Department of Surgery, Osaka University Medical School (H.A., K.O., M.S., J.K., T.K., M.M.); and the Department of Enzyme Biochemistry, Tokyo Metropolitan Institute of Gerontology (S.K.), Japan.
Correspondence to Hideo Ariyoshi, MD, PhD, The Second Department of Surgery, Osaka University Medical School, 2–2 Yamada-oka, Suita, Osaka 565, Japan.
Abstract—Vascular smooth muscle cell
(VSMC) proliferation still remains a poorly understood process,
although it is believed to play a critical role in pathological states,
including atherosclerosis and hypertension. Several
reports have suggested that proteases may be directly involved in this
process; however, it was still unclear which protease is responsible
for VSMC proliferation. In this study, by use of a cell-permeable
calpain inhibitor (calpeptin;
benzyloxycarbonyl-Leu-nLeu-H), its analogue
(benzyloxycarbonyl-Leu-Met-H), the cell-impermeable serine protease
inhibitor leupeptin, and antisense
oligonucleotide against m-calpain to inhibit
proliferation of primarily cultured human VSMCs, we investigated
whether calcium-activated neutral protease (calpain) is
involved in VSMC proliferation. Calpeptin and its analogue, more
specific for m-calpain, equally inhibited the proliferation of VSMCs in
a dose-related manner, whereas a more limited antiproliferative effect
was observed in leupeptin-treated VSMCs. Antisense
oligonucleotide against m-calpain, but not scrambled
antisense, dose-dependently inhibited m-calpain expression and
proliferation of VSMCs. Maximal inhibition was an 
50% reduction of
cell number and m-calpain antigen observed at 50 µmol/L of
antisense oligonucleotide. Calpeptin or antisense
oligonucleotide against m-calpain increased the
expression of the endogenous calpain substrate pp125FAK
(focal adhesion kinase), whereas the expression of the
endogenous calpain inhibitor calpastatin was
not affected. These results suggest that the proliferation of VSMCs
requires protease activity, some of which is due to m-calpain.
Key Words: calpain • vascular smooth muscle cells • proliferation
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