© 1999 American Heart Association, Inc.
Original Contribution |
Liposomal Delivery of Purified Inhibitory-
B
Inhibits Tumor Necrosis Factor-–Induced Human Vascular Smooth Muscle Proliferation
From the Departments of Surgery (C.H.S., B.D.S., S.A.M., X.M., H.A.B., A.H.H., A.B.) and Medicine (L.L.R., A.W., C.A.D.), University of Colorado Health Sciences Center, Denver, Colo.
Correspondence to Craig H. Selzman, MD, Department of Surgery, Campus Box C-320, University of Colorado Health Sciences Center, 4200 East Ninth Ave, Denver, CO 80262. E-mail craig.selzman{at}uchsc.edu
Abstract—Vessel injury results
in the elaboration of various cytokines, including tumor
necrosis factor-
(TNF-), which may influence vascular smooth
muscle cell (VSMC) function and contribute to atherogenesis. We tested
the hypothesis that TNF-–induced VSMC proliferation requires
activation of the transcription factor nuclear factor-
B (NF-B),
which could be prevented by delivery of the NF-B
inhibitory peptide, IB. TNF- induced
concentration-dependent human VSMC proliferation, and neutralizing
antibody to interleukin-6 reduced TNF-–induced VSMC proliferation
by 65%. In TNF-–stimulated VSMCs, there was a 3-fold increase in
NF-B–dependent luciferase reporter activity that was associated
with degradation of IB. To determine an essential role for
NF-B in TNF-–induced VSMC proliferation, recombinant IB
was introduced into VSMCs via liposomal delivery. Under these
conditions, TNF-–induced NF-B nuclear translocation and DNA
binding were inhibited, NF-B–dependent luciferase activity was
reduced by 50%, there was no degradation of native IB
detected, interleukin-6 production was reduced by 54%, and
VSMC proliferation was decreased by 60%. In conclusion, the
mitogenic effect of TNF- on human arterial
VSMCs is dependent on NF-B activation and may be prevented by
exogenously delivered IB. Furthermore, liposomal delivery of
endogenous inhibitory proteins may
represent a novel, therapeutically accessible method for
selective transcriptional suppression in the response to vascular
injury.
Key Words: tumor necrosis factor • nuclear factor-B • inhibitory-B • vascular smooth muscle • cationic liposome
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