The NFkB Inhibitory Peptide, IkBa, 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 (NFkB) is a central transcription factor important in mediating stress and inflammatory-induced signals. We hypothesized that strategies aimed at inhibiting NFkB would abrogate mitogen-induced human VSMC proliferation. Methods. Human aortic VSMC were stimulated with basic fibroblast growth factor (FGF) and tumor necrosis factor-a (TNF), and proliferation was quantified by a colormetric assay. The influence of NFkB on VSMC proliferation was examined by both nonspecific NFkB blockade with calpain inhibitor-1 (CI-1) and dexamethasone (Dex) and specific NFkB blockade with liposomal delivery of the NFkB inhibitory peptide, IkBa. Results. FGF and TNF induced concentrationdependent VSMC proliferation (p < 0.002). Neither CI-1, Dex, nor liposomal IkBa influenced proliferation of unstimulated VSMC. However, both FGFand TNFstimulated VSMC proliferation was inhibited to the level of control with CI-1, Dex, and liposomal IkBa (p < 0.001). Conclusion. The mitogenic effect of FGF and TNF on human arterial VSMC may be prevented by inhibiting NFkB. Furthermore, liposomal delivery of endogenous inhibitory proteins such as IkBa may represent a novel, therapeutically accessible method for selective transcriptional suppression in the response to vascular injury.