© 1998 American Heart Association, Inc.
Original Contributions |
Upregulation of Prostacyclin Synthesis–Related Gene Expression by Shear Stress in Vascular Endothelial Cells
From the Maryland Research Laboratories, Otsuka America Pharmaceutical, Inc, Rockville, Md.
Correspondence to Jun-ichi Kambayashi, MD, PhD, Maryland Research Laboratories, Otsuka America Pharmaceutical, Inc, 9900 Medical Center Dr, Rockville, MD 20850. E-mail junichik{at}mrl.oapi.com
Abstract—Prostacyclin
(prostaglandin I2, PGI2) has a
variety of functions, including inhibition of smooth muscle cell
proliferation, vasodilation, and antiplatelet aggregation.
PGI2 production in endothelial
cells has been reported to increase biphasically after shear loading,
but the underlying mechanism is not well understood. To clarify the
mechanism for the second phase of PGI2 upregulation, we
examined the gene expression of the enzymes involved in
PGI2 production in human umbilical vein
endothelial cells (HUVECs) after shear-stress (24
dyne/cm2) loading. The production of
6-keto-PGF1
, a stable metabolite of PGI2,
increased time-dependently under shear stress. The
arachidonic acid liberation from membrane phospholipids
in HUVECs after 12 hours of shear loading was increased significantly
compared with the static condition. No change was observed for
cytosolic phospholipase A2 expression, as detected by
reverse transcription–polymerase chain reaction and Western blotting.
Cyclooxygenase (COX)-1 mRNA increased after 1 hour
of shear loading, and the increase lasted for 12 hours, the longest
time tested, whereas COX-2 mRNA increased after 1 hour of shear loading
and peaked at 6 hours. An increase of COX-1 expression was detected at
12 hours of shear loading by Western blotting. No expression of COX-2
was detected in the static control, but induced expression was observed
at 6 hours after shear loading. PGI2 synthase was also
found to be upregulated. These results suggest that the elevated
PGI2 production by shear stress is mediated by
increased arachidonic acid release and a combination of
increased expression of COXs and PGI2 synthase.
Key Words: shear stress • prostacyclin • gene regulation • endothelial cells
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