The NFkappaB inhibitory peptide, IkappaBalpha, prevents human vascular smooth muscle proliferation.
BACKGROUND
Vessel injury results in an inflammatory response characterized by the elaboration of cytokines and growth factors, which ultimately influence vascular smooth muscle cell (VSMC) growth and contribute to atherogenesis. Nuclear factor-kappa B (NFkappaB) is a central transcription factor important in mediating stress and inflammatory-induced signals. We hypothesized that strategies aimed at inhibiting NFkappaB would abrogate mitogen-induced human VSMC proliferation.


METHODS
Human aortic VSMC were stimulated with basic fibroblast growth factor (FGF) and tumor necrosis factor-alpha (TNF), and proliferation was quantified by a colormetric assay. The influence of NFkappaB on VSMC proliferation was examined by both nonspecific NFkappaB blockade with calpain inhibitor-1 (CI-1) and dexamethasone (Dex) and specific NFkappaB blockade with liposomal delivery of the NFkappaB inhibitory peptide, IkappaBalpha.


RESULTS
FGF and TNF induced concentration-dependent VSMC proliferation (p < 0.002). Neither CI-1, Dex, nor liposomal IkappaBalpha influenced proliferation of unstimulated VSMC. However, both FGF- and TNF-stimulated VSMC proliferation was inhibited to the level of control with CI-1, Dex, and liposomal IkappaBalpha (p < 0.001).


CONCLUSIONS
The mitogenic effect of FGF and TNF on human arterial VSMC may be prevented by inhibiting NFkappaB. Furthermore, liposomal delivery of endogenous inhibitory proteins such as IkappaBalpha may represent a novel, therapeutically accessible method for selective transcriptional suppression in the response to vascular injury.
Selzman
C H
CH
Department of Surgery, University of Colorado Health Sciences Center, Denver 80262, USA. craig.selzman@UCHSC.edu
Shames
B D
BD
McIntyre
R C
RC
Banerjee
A
A
Harken
A H
AH
D001011:Aorta / Q000378:metabolism*; D002154:Calpain / Q000037:antagonists & inhibitors; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000494:pharmacology* / Q000502:physiology*; D003907:Dexamethasone / Q000494:pharmacology; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D006801:Humans; D020672:I-kappa B Proteins; D008081:Liposomes; D008934:Mitogens / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D008081:Liposomes; D008934:Mitogens; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D005346:Fibroblast Growth Factors; D003907:Dexamethasone; D002154:Calpain